HMGCS2D
MCID: 3HY011
MIFTS: 31

3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency (HMGCS2D)

Categories: Genetic diseases, Liver diseases, Metabolic diseases, Rare diseases

Aliases & Classifications for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

MalaCards integrated aliases for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency:

Name: 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency 57 72
Hmg-Coa Synthase Deficiency 58 72 36
Hmgcs2 Deficiency 57 72 6
Mitochondrial Hmg-Coa Synthase Deficiency 57 72
Hmg-Coa Synthase-2 Deficiency 57 13
Hmgcs2d 57 72
Mitochondrial 3-Hydroxy-3-Methylglutaryl-Coa Synthase 2 Deficiency 72
3-Hydroxy-3-Methylglutaryl-Coa Synthase Deficiency, Type 2 39
3-Hydroxy-3-Methylglutaryl-Coa Synthase 2 Deficiency 70
3-Hydroxy-3-Methylglutaryl-Coa Synthase Deficiency 58
Hmgcs Deficiency 72

Characteristics:

Orphanet epidemiological data:

58
3-hydroxy-3-methylglutaryl-coa synthase deficiency
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Childhood;

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal recessive

Miscellaneous:
diagnosis is difficult outside fasting because biochemical analyses give normal results and enzyme studies can only be performed in biopsied liver


HPO:

31
3-hydroxy-3-methylglutaryl-coa synthase-2 deficiency:
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Inborn errors of metabolism


External Ids:

OMIM® 57 605911
KEGG 36 H01123
ICD10 via Orphanet 33 E71.3
UMLS via Orphanet 71 C2751532
Orphanet 58 ORPHA35701
MedGen 41 C2751532
UMLS 70 C2751532

Summaries for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

KEGG : 36 HMG-CoA synthase (HMGCS) deficiency is a autosomal recessive disorder of ketogenesis. Two isoforms of HMGCS are found in higher eukaryotes: the cytosolic HMGCS1 and mitochondrial HMGCS2. Mitochondrial HMGCS2 is involved in hepatic ketogenesis, and HMGCS2 deficiency causes hypoketotic hypoglycaemia after prolonged fasting. To date, no mutations have been identified in the human cytosolic HMGCS1.

MalaCards based summary : 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency, also known as hmg-coa synthase deficiency, is related to fatty liver disease and hypoglycemia, and has symptoms including vomiting and diarrhea. An important gene associated with 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency is HMGCS2 (3-Hydroxy-3-Methylglutaryl-CoA Synthase 2), and among its related pathways/superpathways are Synthesis and degradation of ketone bodies and Valine, leucine and isoleucine degradation. Affiliated tissues include liver, and related phenotypes are hypoglycemia and seizure

OMIM® : 57 Mitochondrial HMG-CoA synthase deficiency is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies. Patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting (summary by Aledo et al., 2006). (605911) (Updated 05-Apr-2021)

UniProtKB/Swiss-Prot : 72 3-hydroxy-3-methylglutaryl-CoA synthase-2 deficiency: A metabolic disorder characterized by severe hypoketotic hypoglycemia, encephalopathy, and hepatomegaly.

Related Diseases for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Diseases related to 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 14)
# Related Disease Score Top Affiliating Genes
1 fatty liver disease 10.6
2 hypoglycemia 10.6
3 hypertriglyceridemia, familial 10.5
4 autosomal recessive disease 10.5
5 ocular motor apraxia 10.4
6 inherited metabolic disorder 10.4
7 alpha-methylacetoacetic aciduria 10.3
8 carbonic anhydrase va deficiency, hyperammonemia due to 10.3
9 hemophagocytic lymphohistiocytosis 10.3
10 lactic acidosis 10.3
11 metabolic acidosis 10.2
12 hypoglycemic coma 10.2
13 lipid metabolism disorder 10.2
14 encephalopathy 10.2

Graphical network of the top 20 diseases related to 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency:



Diseases related to 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Symptoms & Phenotypes for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Human phenotypes related to 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency:

58 31 (show all 7)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hypoglycemia 58 31 hallmark (90%) Very frequent (99-80%) HP:0001943
2 seizure 31 hallmark (90%) HP:0001250
3 seizures 58 Very frequent (99-80%)
4 hepatomegaly 31 HP:0002240
5 vomiting 31 HP:0002013
6 abnormality of metabolism/homeostasis 58 Very frequent (99-80%)
7 diarrhea 31 HP:0002014

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Abdomen Liver:
hepatomegaly
fatty infiltration
hmg-coa synthase activity approximately 10% of normal

Metabolic Features:
hypoketotic hypoglycemia when fasting

Abdomen Gastrointestinal:
vomiting
diarrhea
gastroenteritis
poor food intake

Laboratory Abnormalities:
highly elevated free fatty acids

Clinical features from OMIM®:

605911 (Updated 05-Apr-2021)

UMLS symptoms related to 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency:


vomiting; diarrhea

Drugs & Therapeutics for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Search Clinical Trials , NIH Clinical Center for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Genetic Tests for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Anatomical Context for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

MalaCards organs/tissues related to 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency:

40
Liver

Publications for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Articles related to 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency:

(show all 14)
# Title Authors PMID Year
1
Genetic basis of mitochondrial HMG-CoA synthase deficiency. 57 6
11479731 2001
2
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients. 57 6
11228257 2001
3
Hepatic mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme a synthase deficiency. 57 6
9727719 1998
4
Fasting hypoketotic coma in a child with deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. 6 57
9337379 1997
5
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations. 6
25511235 2015
6
New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. 6
23751782 2013
7
Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design. 6
20346956 2010
8
Refining the diagnosis of mitochondrial HMG-CoA synthase deficiency. 57
16601895 2006
9
Splicing in action: assessing disease causing sequence changes. 6
16199547 2005
10
Mitochondrial HMG-CoA synthase deficiency: identification of two further patients carrying two novel mutations. 6
12647205 2003
11
The diagnosis of mitochondrial HMG-CoA synthase deficiency. 6
12072887 2002
12
Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency. 61
33045405 2020
13
Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Unique Presenting Laboratory Values and a Review of Biochemical and Clinical Features. 61
29030856 2018
14
Genotype-based databases for variants causing rare diseases. 61
25111118 2014

Variations for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

ClinVar genetic disease variations for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency:

6 (show top 50) (show all 94)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 HMGCS2 NC_000001.11:g.(?_119768721)_(119768864_?)del Deletion Pathogenic 832206 GRCh37: 1:120311344-120311487
GRCh38:
2 HMGCS2 NM_001166107.1(HMGCS2):c.724+2T>C SNV Pathogenic 644135 rs1571037298 GRCh37: 1:120301739-120301739
GRCh38: 1:119759116-119759116
3 HMGCS2 NM_005518.4(HMGCS2):c.181_182insCCAATATGGCCCTGGAGGCCAA (p.Val61fs) Insertion Pathogenic 915425 GRCh37: 1:120307172-120307173
GRCh38: 1:119764549-119764550
4 HMGCS2 NM_005518.4(HMGCS2):c.1480C>T (p.Arg494Ter) SNV Pathogenic 827683 GRCh37: 1:120293472-120293472
GRCh38: 1:119750849-119750849
5 HMGCS2 NM_001166107.1(HMGCS2):c.500A>G (p.Tyr167Cys) SNV Pathogenic 9262 rs137852640 GRCh37: 1:120306854-120306854
GRCh38: 1:119764231-119764231
6 HMGCS2 NM_001166107.1(HMGCS2):c.646del (p.Ser216fs) Deletion Pathogenic 488533 rs1553240525 GRCh37: 1:120301819-120301819
GRCh38: 1:119759196-119759196
7 HMGCS2 NM_001166107.1(HMGCS2):c.891-2del Deletion Pathogenic 488532 rs1553240165 GRCh37: 1:120298222-120298222
GRCh38: 1:119755599-119755599
8 HMGCS2 NC_000001.11:g.(?_119768741)_(119768844_?)del Deletion Pathogenic 650721 GRCh37: 1:120311364-120311467
GRCh38: 1:119768741-119768844
9 HMGCS2 NM_005518.4(HMGCS2):c.559+1G>A SNV Pathogenic 859738 GRCh37: 1:120306794-120306794
GRCh38: 1:119764171-119764171
10 HMGCS2 NM_005518.4(HMGCS2):c.682C>T (p.Arg228Ter) SNV Pathogenic 1028892 GRCh37: 1:120302490-120302490
GRCh38: 1:119759867-119759867
11 HMGCS2 NM_005518.4(HMGCS2):c.726C>G (p.Tyr242Ter) SNV Pathogenic 1028893 GRCh37: 1:120301865-120301865
GRCh38: 1:119759242-119759242
12 HMGCS2 NM_005518.4(HMGCS2):c.810C>G (p.Tyr270Ter) SNV Pathogenic 1034181 GRCh37: 1:120301781-120301781
GRCh38: 1:119759158-119759158
13 HMGCS2 NM_005518.4(HMGCS2):c.1090T>A (p.Phe364Ile) SNV Likely pathogenic 859739 GRCh37: 1:120298147-120298147
GRCh38: 1:119755524-119755524
14 HMGCS2 NM_001166107.1(HMGCS2):c.560-633G>A SNV Likely pathogenic 9259 rs137852638 GRCh37: 1:120302538-120302538
GRCh38: 1:119759915-119759915
15 HMGCS2 NM_001166107.1(HMGCS2):c.1061+1G>C SNV Likely pathogenic 590814 rs764706394 GRCh37: 1:120298049-120298049
GRCh38: 1:119755426-119755426
16 HMGCS2 NM_005518.4(HMGCS2):c.512C>T (p.Ala171Val) SNV Likely pathogenic 870423 GRCh37: 1:120306842-120306842
GRCh38: 1:119764219-119764219
17 HMGCS2 NM_005518.4(HMGCS2):c.905C>T (p.Thr302Ile) SNV Likely pathogenic 870424 GRCh37: 1:120300007-120300007
GRCh38: 1:119757384-119757384
18 HMGCS2 NM_001166107.1(HMGCS2):c.1373G>A (p.Arg458His) SNV Conflicting interpretations of pathogenicity 9260 rs137852639 GRCh37: 1:120293453-120293453
GRCh38: 1:119750830-119750830
19 HMGCS2 NM_005518.4(HMGCS2):c.111T>C (p.Ser37=) SNV Conflicting interpretations of pathogenicity 713190 rs200675569 GRCh37: 1:120307243-120307243
GRCh38: 1:119764620-119764620
20 HMGCS2 NM_001166107.1(HMGCS2):c.560-646C>T SNV Conflicting interpretations of pathogenicity 292336 rs886045207 GRCh37: 1:120302551-120302551
GRCh38: 1:119759928-119759928
21 HMGCS2 NM_001166107.1(HMGCS2):c.174C>T (p.Ala58=) SNV Conflicting interpretations of pathogenicity 292340 rs138739620 GRCh37: 1:120307180-120307180
GRCh38: 1:119764557-119764557
22 HMGCS2 NM_001166107.1(HMGCS2):c.1376G>C (p.Arg459Pro) SNV Conflicting interpretations of pathogenicity 452101 rs372079931 GRCh37: 1:120293450-120293450
GRCh38: 1:119750827-119750827
23 HMGCS2 NM_001166107.1(HMGCS2):c.560-697C>T SNV Conflicting interpretations of pathogenicity 389052 rs201735169 GRCh37: 1:120302602-120302602
GRCh38: 1:119759979-119759979
24 HMGCS2 NM_001166107.1(HMGCS2):c.364G>A (p.Asp122Asn) SNV Uncertain significance 203780 rs368014391 GRCh37: 1:120306990-120306990
GRCh38: 1:119764367-119764367
25 HMGCS2 NM_005518.4(HMGCS2):c.50C>T (p.Ala17Val) SNV Uncertain significance 850237 GRCh37: 1:120311418-120311418
GRCh38: 1:119768795-119768795
26 HMGCS2 NM_001166107.1(HMGCS2):c.241G>A (p.Ala81Thr) SNV Uncertain significance 426647 rs151187711 GRCh37: 1:120307113-120307113
GRCh38: 1:119764490-119764490
27 HMGCS2 NM_005518.4(HMGCS2):c.1082A>G (p.Gln361Arg) SNV Uncertain significance 956217 GRCh37: 1:120298155-120298155
GRCh38: 1:119755532-119755532
28 HMGCS2 NM_005518.4(HMGCS2):c.146C>T (p.Thr49Ile) SNV Uncertain significance 959097 GRCh37: 1:120307208-120307208
GRCh38: 1:119764585-119764585
29 HMGCS2 NM_001166107.1(HMGCS2):c.725-14G>A SNV Uncertain significance 292335 rs188523700 GRCh37: 1:120300075-120300075
GRCh38: 1:119757452-119757452
30 HMGCS2 NM_001166107.1(HMGCS2):c.358C>A (p.Pro120Thr) SNV Uncertain significance 596883 rs758033248 GRCh37: 1:120306996-120306996
GRCh38: 1:119764373-119764373
31 HMGCS2 NM_001166107.1(HMGCS2):c.73C>G (p.Pro25Ala) SNV Uncertain significance 203778 rs144744634 GRCh37: 1:120311395-120311395
GRCh38: 1:119768772-119768772
32 HMGCS2 NM_005518.4(HMGCS2):c.803G>A (p.Arg268Gln) SNV Uncertain significance 874560 GRCh37: 1:120301788-120301788
GRCh38: 1:119759165-119759165
33 HMGCS2 NM_005518.4(HMGCS2):c.103A>G (p.Arg35Gly) SNV Uncertain significance 1003176 GRCh37: 1:120311365-120311365
GRCh38: 1:119768742-119768742
34 HMGCS2 NM_001166107.1(HMGCS2):c.520T>C (p.Phe174Leu) SNV Uncertain significance 9257 rs137852636 GRCh37: 1:120306834-120306834
GRCh38: 1:119764211-119764211
35 HMGCS2 NM_001166107.1(HMGCS2):c.560-672G>A SNV Uncertain significance 292337 rs150140061 GRCh37: 1:120302577-120302577
GRCh38: 1:119759954-119759954
36 HMGCS2 NM_001166107.1(HMGCS2):c.1387C>T (p.Arg463Trp) SNV Uncertain significance 292328 rs780044819 GRCh37: 1:120293439-120293439
GRCh38: 1:119750816-119750816
37 HMGCS2 NM_001166107.1(HMGCS2):c.346C>T (p.Arg116Cys) SNV Uncertain significance 203779 rs200607527 GRCh37: 1:120307008-120307008
GRCh38: 1:119764385-119764385
38 HMGCS2 NM_001166107.1(HMGCS2):c.664C>T (p.Arg222Trp) SNV Uncertain significance 663113 rs773945291 GRCh37: 1:120301801-120301801
GRCh38: 1:119759178-119759178
39 HMGCS2 NM_005518.4(HMGCS2):c.880G>A (p.Asp294Asn) SNV Uncertain significance 838873 GRCh37: 1:120300032-120300032
GRCh38: 1:119757409-119757409
40 HMGCS2 NM_005518.4(HMGCS2):c.502G>A (p.Gly168Ser) SNV Uncertain significance 839670 GRCh37: 1:120306852-120306852
GRCh38: 1:119764229-119764229
41 HMGCS2 NM_005518.4(HMGCS2):c.560-3C>T SNV Uncertain significance 947924 GRCh37: 1:120302615-120302615
GRCh38: 1:119759992-119759992
42 HMGCS2 NM_005518.4(HMGCS2):c.412T>C (p.Ser138Pro) SNV Uncertain significance 949754 GRCh37: 1:120306942-120306942
GRCh38: 1:119764319-119764319
43 HMGCS2 NM_005518.4(HMGCS2):c.1095C>G (p.Asp365Glu) SNV Uncertain significance 964690 GRCh37: 1:120298142-120298142
GRCh38: 1:119755519-119755519
44 HMGCS2 NM_005518.4(HMGCS2):c.586G>C (p.Asp196His) SNV Uncertain significance 1016311 GRCh37: 1:120302586-120302586
GRCh38: 1:119759963-119759963
45 HMGCS2 NM_005518.4(HMGCS2):c.245G>A (p.Gly82Glu) SNV Uncertain significance 1026454 GRCh37: 1:120307109-120307109
GRCh38: 1:119764486-119764486
46 HMGCS2 NM_001166107.1(HMGCS2):c.768G>A (p.Met256Ile) SNV Uncertain significance 570841 rs138086607 GRCh37: 1:120300018-120300018
GRCh38: 1:119757395-119757395
47 HMGCS2 NM_005518.4(HMGCS2):c.428C>G (p.Thr143Arg) SNV Uncertain significance 961578 GRCh37: 1:120306926-120306926
GRCh38: 1:119764303-119764303
48 HMGCS2 NM_001166107.1(HMGCS2):c.160G>A (p.Val54Met) SNV Uncertain significance 9261 rs28937320 GRCh37: 1:120307194-120307194
GRCh38: 1:119764571-119764571
49 HMGCS2 NM_005518.4(HMGCS2):c.791G>A (p.Arg264Gln) SNV Uncertain significance 874561 GRCh37: 1:120301800-120301800
GRCh38: 1:119759177-119759177
50 HMGCS2 NM_001166107.1(HMGCS2):c.26A>G (p.Lys9Arg) SNV Uncertain significance 292346 rs144004292 GRCh37: 1:120311442-120311442
GRCh38: 1:119768819-119768819

UniProtKB/Swiss-Prot genetic disease variations for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency:

72 (show all 19)
# Symbol AA change Variation ID SNP ID
1 HMGCS2 p.Phe174Leu VAR_032711 rs137852636
2 HMGCS2 p.Val54Met VAR_032757 rs28937320
3 HMGCS2 p.Tyr167Cys VAR_032758 rs137852640
4 HMGCS2 p.Gly212Arg VAR_032759 rs137852638
5 HMGCS2 p.Arg500His VAR_032760 rs137852639
6 HMGCS2 p.Arg112Trp VAR_083500 rs768707273
7 HMGCS2 p.Val144Leu VAR_083501 rs775528207
8 HMGCS2 p.Gly168Ser VAR_083502 rs746217014
9 HMGCS2 p.Gly169Asp VAR_083503 rs123722687
10 HMGCS2 p.Trp185Arg VAR_083504
11 HMGCS2 p.Arg188His VAR_083505 rs761373362
12 HMGCS2 p.Gly232Val VAR_083506 rs100254881
13 HMGCS2 p.Leu266Ser VAR_083507 rs918691885
14 HMGCS2 p.Met307Thr VAR_083508
15 HMGCS2 p.Ser360Pro VAR_083509
16 HMGCS2 p.Gly388Arg VAR_083510 rs752626288
17 HMGCS2 p.Phe470Thr VAR_083512
18 HMGCS2 p.Tyr503Cys VAR_083513
19 HMGCS2 p.Arg505Gln VAR_083514 rs758519315

Expression for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Search GEO for disease gene expression data for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency.

Pathways for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Pathways related to 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency according to KEGG:

36
# Name Kegg Source Accession
1 Synthesis and degradation of ketone bodies hsa00072
2 Valine, leucine and isoleucine degradation hsa00280
3 Butanoate metabolism hsa00650
4 Terpenoid backbone biosynthesis hsa00900

GO Terms for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

Sources for 3-Hydroxy-3-Methylglutaryl-Coa Synthase-2 Deficiency

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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