NM_005518.4(HMGCS2):c.1502G>C (p.Arg501Pro) AND 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Sep 18, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000805374.14

Allele description [Variation Report for NM_005518.4(HMGCS2):c.1502G>C (p.Arg501Pro)]

NM_005518.4(HMGCS2):c.1502G>C (p.Arg501Pro)

Gene:

HMGCS2:3-hydroxy-3-methylglutaryl-CoA synthase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p12

Genomic location:

Preferred name:

NM_005518.4(HMGCS2):c.1502G>C (p.Arg501Pro)

HGVS:

NC_000001.11:g.119750827C>G
NG_013348.1:g.23106G>C
NM_001166107.1:c.1376G>C
NM_005518.4:c.1502G>CMANE SELECT
NP_001159579.1:p.Arg459Pro
NP_005509.1:p.Arg501Pro
NP_005509.1:p.Arg501Pro
LRG_447t1:c.1502G>C
LRG_447t2:c.1376G>C
LRG_447:g.23106G>C
LRG_447p1:p.Arg501Pro
LRG_447p2:p.Arg459Pro
NC_000001.10:g.120293450C>G
NM_005518.3:c.1502G>C

Protein change:

R459P; ARG501PRO

Links:

OMIM: 600234.0009; dbSNP: rs372079931

NCBI 1000 Genomes Browser:

rs372079931

Molecular consequence:

NM_001166107.1:c.1376G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005518.4:c.1502G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (HMGCS2D)
Synonyms:: HMGCS2 DEFICIENCY; MITOCHONDRIAL HMG-CoA SYNTHASE DEFICIENCY; mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011614; MedGen: C2751532; Orphanet: 35701; OMIM: 605911

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000945328	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 2, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 33045405, 31910233, 30477625, 28492532
SCV001189983	Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 15, 2020)	maternal	research
SCV001761662	OMIM	no assertion criteria provided	Pathogenic (Jul 27, 2021)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 33045405, 31910233
SCV003842126	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 33045405, 30477625, 31910233, 25741868
SCV005395412	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Sep 18, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31910233, 33045405, 38469099 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Thai	maternal	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

[Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase deficiency: a case report and literature review].

Ma D, Yu D.

Zhongguo Dang Dai Er Ke Za Zhi. 2018 Nov;20(11):930-933. Review. Chinese.

PubMed [citation]

PMID:: 30477625
PMCID:: PMC7389032

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000945328.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 501 of the HMGCS2 protein (p.Arg501Pro). This variant is present in population databases (rs372079931, gnomAD 0.01%). This missense change has been observed in individual(s) with HMG-CoA synthase deficiency (PMID: 33045405; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 452101). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HMGCS2 protein function. Experimental studies have shown that this missense change affects HMGCS2 function (PMID: 31910233). This variant disrupts the p.Arg501 amino acid residue in HMGCS2. Other variant(s) that disrupt this residue have been observed in individuals with HMGCS2-related conditions (PMID: 30477625), which suggests that this may be a clinically significant amino acid residue.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University, SCV001189983.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Thai	1	not provided	not provided	research	not provided

Description

The patient is affected with Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) and harbors the compound heterozygous HMGCS2 mutations, c.1480C>T, p.Arg494* (SCV 001169710 assigned) inherited from his father and c.1502G>C, p.Arg501Pro from his mother.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	maternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From OMIM, SCV001761662.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 Thai patients with mitochondrial HMG-CoA synthase deficiency (HMGCS2D; 605911), Rojnueangnit et al. (2020) identified compound heterozygous mutations in the HMGCS2 gene. Both patients carried a c.1502G-C transition (c.1502G-C, NM_005518.3), resulting in an arg501-to-pro (R501P) substitution, on one allele; on the other allele, patient 1 carried a c.1480C-T transition, resulting in an arg494-to-ter (R494X; 600234.0010) substitution, and patient 2 carried a c.520C-T transition, resulting in a phe174-to-leu (F174L; 600234.0001) substitution. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents in both families were shown to be carriers. The R494X mutation was present in the gnomAD database in 2 of 282,752 alleles. The R501P mutation was present in the gnomAD database in 3 of 251,332 alleles and had an allele frequency of 0.42% in an in-house Thai exome database. Bagheri-Fam et al. (2020) expressed HMGCS2 with the R501P mutation in E. coli and showed that it lacked enzymatic activity.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003842126.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with HMGCS2 related disorder (PMID: 33045405). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 31910233, 33045405). A different missense change at the same codon (p.Arg501Gln) has been reported to be associated with HMGCS2 related disorder (PMID: 30477625). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005395412.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: HMGCS2 c.1502G>C (p.Arg501Pro) results in a non-conservative amino acid change located in the Hydroxymethylglutaryl-coenzyme A synthase, C-terminal domain (IPR013746) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251332 control chromosomes. c.1502G>C has been reported in the literature in compound heterozygous individuals affected with 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (e.g. Rojnueangnit_2020, Williams_2024). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absent 3-hydroxy-3-methylglutaryl CoA synthase activity in vitro (Bagheri-Fam_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31910233, 33045405, 38469099). ClinVar contains an entry for this variant (Variation ID: 452101). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 18, 2024

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