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.
NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
Pathogenic (11)
Pathogenic (11)
11 out of 17 submissions contributed to this classification
Help
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.
17
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: VCV000011957.35
- 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 Oct 25, 2025 Feb 21, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_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 - Protein change
- R41Q
- Other names
- -
- Canonical SPDI
- NC_000001.11:23820531:C:T
-
Global minor allele
frequency (GMAF) HelpThe 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.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00007
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
581 | 598 | |
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. |
|---|---|---|---|---|
| Pathogenic (12) |
criteria provided, multiple submitters, no conflicts
|
Feb 21, 2025 | RCV000012735.36 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 1, 2020 | RCV000078342.21 | |
| 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. |
Expand all rows
Collapse all rows
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 08, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919522.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Feb 12, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
Revvity Omics, Revvity
Accession: SCV002025005.4
First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(-)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
Pathology and Clinical Laboratory Medicine, King Fahad Medical City
Accession: SCV000996288.1
First in ClinVar: Oct 19, 2019 Last updated: Oct 19, 2019 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 12
Ethnicity/Population group: Arab
Geographic origin: Middle East
|
|
|
Pathogenic
(Mar 21, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
Fulgent Genetics, Fulgent Genetics
Accession: SCV002781040.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Apr 11, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
Genome-Nilou Lab
Accession: SCV004172770.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
|
|
Pathogenic
(Mar 17, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
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 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Mar 12, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
Baylor Genetics
Accession: SCV001524522.2
First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jun 01, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV005628351.1
First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jul 05, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001209850.6
First in ClinVar: Apr 15, 2020 Last updated: Feb 25, 2025 |
Comment:
show
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)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 18, 2013)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000110188.9
First in ClinVar: Jan 17, 2014 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 7
Zygosity: 1 Homozygote, 7 Single Heterozygotes
Sex: mixed
|
|
|
Pathogenic
(Feb 21, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
3billion
Accession: SCV006585267.1
First in ClinVar: Oct 25, 2025 Last updated: Oct 25, 2025 |
Comment:
show
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: Missense variant. The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15122894). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011957 /PMID: 9463337). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28488182, 9463337). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Method: exome sequencing
|
|
|
Pathogenic
(Oct 13, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Deficiency of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase |
Natera, Inc.
Accession: SCV002094168.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
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 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Likely pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001957794.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Feb 01, 1998)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
HMG-CoA LYASE DEFICIENCY |
OMIM
Accession: SCV000032970.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
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
(Aug 25, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132938.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Mar 08, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Deficiency of hydroxymethylglutaryl-CoA lyase |
Counsyl
Accession: SCV000790225.2
First in ClinVar: Oct 11, 2015 Last updated: Jun 29, 2025 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
Comment:
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.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: Missense variant. The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 15122894). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.96 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011957 /PMID: 9463337). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 28488182, 9463337). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
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.
Citations for germline classification of this variant
Help| 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 ...
HelpThese 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 06, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.