VCV000011957.33 - ClinVar

NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

10 out of 16 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)

Variation ID: 11957 Accession: VCV000011957.33

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.11 1: 23820532 (GRCh38) [ NCBI UCSC ] 1: 24147022 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	May 13, 2015	Jun 29, 2025	Jul 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000191.3:c.122G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000182.2:p.Arg41Gln	missense
NM_001166059.2:c.122G>A	NP_001159531.1:p.Arg41Gln	missense
NC_000001.11:g.23820532C>T
NC_000001.10:g.24147022C>T
NG_013061.1:g.9928G>A
	P35914:p.Arg41Gln

... more HGVS ... less HGVS

Protein change

R41Q

Other names

Canonical SPDI

NC_000001.11:23820531:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD) 0.00004

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00007

Links

ClinGen: CA220476 UniProtKB: P35914#VAR_003744 OMIM: 613898.0004 dbSNP: rs121964997 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HMGCL		-	-	GRCh38 GRCh37	534	552

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Deficiency of hydroxymethylglutaryl-CoA lyase	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Jul 5, 2024	RCV000012735.34
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jun 1, 2020	RCV000078342.21
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency	Pathogenic (1)	no assertion criteria provided	Oct 13, 2020	RCV001831566.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Mar 31, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002025005.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024

Pathogenic (Mar 17, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: germline	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre Accession: SCV004804931.2 First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024

Pathogenic (Jan 18, 2013) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110188.9 First in ClinVar: Jan 17, 2014 Last updated: Apr 13, 2025	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HMGCL Number of individuals with the variant: 7 Zygosity: Homozygote, Single Heterozygote Sex: mixed

Pathogenic (Mar 08, 2018) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000919522.1 First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019	Publications: PubMed (1) PubMed: 17173698 Comment: Variant summary: HMGCL c.122G>A (p.Arg41Gln) results in a conservative amino acid change located in the Pyruvate carboxyltransferase of the encoded protein sequence. Four of five … (more) Variant summary: HMGCL c.122G>A (p.Arg41Gln) results in a conservative amino acid change located in the Pyruvate carboxyltransferase of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant, c.122G>A, has been reported in the literature in multiple individuals affected with HMG-CoA Lyase Deficiency and has been indicated to be a Saudi Arabian founder mutation (Al-Sayed_2006) . These data indicate that the variant is very likely to be associated with disease. A clinical diagnostic laboratory classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: yes Allele origin: germline	Pathology and Clinical Laboratory Medicine, King Fahad Medical City Accession: SCV000996288.1 First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019	Number of individuals with the variant: 12 Ethnicity/Population group: Arab Geographic origin: Middle East

Pathogenic (Mar 12, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001524522.2 First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024

Pathogenic (Jun 01, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005628351.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025	Comment: Functional studies found that R41Q is associated with significantly diminished 3-hydroxy-3-methylglutaryl-CoA lyase activity compared to wild-type (PMID: 15122894); In silico analysis supports that this missense … (more) Functional studies found that R41Q is associated with significantly diminished 3-hydroxy-3-methylglutaryl-CoA lyase activity compared to wild-type (PMID: 15122894); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 24969942, 9463337, 17173698, 14518825, 28488182, 29427439, 31589614, 33996180, 35646072, 17692550, 15122894) (less)

Pathogenic (Mar 21, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV002781040.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025

Pathogenic (Jul 05, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001209850.6 First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025	Publications: PubMed (5) PubMed: 9463337‚ 14518825‚ 17173698‚ 28488182‚ 15122894 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 41 of the HMGCL protein (p.Arg41Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 41 of the HMGCL protein (p.Arg41Gln). This variant is present in population databases (rs121964997, gnomAD 0.01%). This missense change has been observed in individual(s) with 3HMG-CoA Lyase deficiency (PMID: 9463337, 14518825, 17173698, 28488182). ClinVar contains an entry for this variant (Variation ID: 11957). 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 HMGCL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMGCL function (PMID: 9463337, 15122894). For these reasons, this variant has been classified as Pathogenic. (less)

Pathogenic (Apr 11, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004172770.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023

Pathogenic (Aug 25, 2019) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001132938.1 First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020

Pathogenic (Feb 01, 1998) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	HMG-CoA LYASE DEFICIENCY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032970.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 9463337 Comment on evidence: Among 9 Saudi probands with HMG-CoA lyase deficiency (HMGCLD; 246450), Mitchell et al. (1998) found genetic diversity: 6 were homozygous for the missense mutation arg41 … (more) Among 9 Saudi probands with HMG-CoA lyase deficiency (HMGCLD; 246450), Mitchell et al. (1998) found genetic diversity: 6 were homozygous for the missense mutation arg41 to gln (R41Q), and 2 were homozygous for a deletion of 2 nucleotides at codon 305 resulting in a frameshift (Phe305fs(-2); 613898.0006) in the HMGCLD gene. Mitchell et al. (1998) used a bacterial expression system for rapid screening of the activity of HL mutant proteins. They pointed out that codons 41 and 42 are important for normal HMGCL catalysis and accounted for a disproportionate 21 (26%) of 82 mutant alleles in their group of HL-deficient probands. (less)

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739924.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021

Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001957794.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Pathogenic (Oct 13, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Deficiency of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002094168.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022

Pathogenic (Mar 08, 2017) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Deficiency of hydroxymethylglutaryl-CoA lyase Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790225.2 First in ClinVar: Oct 11, 2015 Last updated: Jun 29, 2025	Publications: PubMed (2) PubMed: 9463337‚ 17173698 Comment: This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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Comment:

Variant summary: HMGCL c.122G>A (p.Arg41Gln) results in a conservative amino acid change located in the Pyruvate carboxyltransferase of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant, c.122G>A, has been reported in the literature in multiple individuals affected with HMG-CoA Lyase Deficiency and has been indicated to be a Saudi Arabian founder mutation (Al-Sayed_2006) . These data indicate that the variant is very likely to be associated with disease. A clinical diagnostic laboratory classifies the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Functional studies found that R41Q is associated with significantly diminished 3-hydroxy-3-methylglutaryl-CoA lyase activity compared to wild-type (PMID: 15122894); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 24969942, 9463337, 17173698, 14518825, 28488182, 29427439, 31589614, 33996180, 35646072, 17692550, 15122894)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 41 of the HMGCL protein (p.Arg41Gln). This variant is present in population databases (rs121964997, gnomAD 0.01%). This missense change has been observed in individual(s) with 3HMG-CoA Lyase deficiency (PMID: 9463337, 14518825, 17173698, 28488182). ClinVar contains an entry for this variant (Variation ID: 11957). 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 HMGCL protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HMGCL function (PMID: 9463337, 15122894). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Successful Management of Pregnancies in Patients with Inherited Disorders of Ketone Body Metabolism.	Sulaiman RA	JIMD reports	2018	PMID: 28488182
Mutations underlying 3-hydroxy-3-methylglutaryl CoA lyase deficiency in the Saudi population.	Al-Sayed M	BMC medical genetics	2006	PMID: 17173698
Evaluation of 3-hydroxy-3-methylglutaryl-coenzyme A lyase arginine-41 as a catalytic residue: use of acetyldithio-coenzyme A to monitor product enolization.	Tuinstra RL	Biochemistry	2004	PMID: 15122894
Biochemical and molecular analyses in three patients with 3-hydroxy-3-methylglutaric aciduria.	Pospísilová E	Journal of inherited metabolic disease	2003	PMID: 14518825
HMG CoA lyase deficiency: identification of five causal point mutations in codons 41 and 42, including a frequent Saudi Arabian mutation, R41Q.	Mitchell GA	American journal of human genetics	1998	PMID: 9463337
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HMGCL	-	-	-	-

Text-mined citations for rs121964997 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 05, 2025

ClinVar Genomic variation as it relates to human health

NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121964997 ...