ClinVar Genomic variation as it relates to human health
NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000191.3(HMGCL):c.122G>A (p.Arg41Gln)
Variation ID: 11957 Accession: VCV000011957.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.11 1: 23820532 (GRCh38) [ NCBI UCSC ] 1: 24147022 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 6, 2024 Mar 17, 2024 - HGVS
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Nucleotide 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
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- Canonical SPDI
- NC_000001.11:23820531:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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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
The Genome Aggregation Database (gnomAD), exomes 0.00002
Exome Aggregation Consortium (ExAC) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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HMGCL | - | - |
GRCh38 GRCh37 |
502 | 516 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (11) |
criteria provided, multiple submitters, no conflicts
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Mar 17, 2024 | RCV000012735.28 | |
Pathogenic (3) |
criteria provided, single submitter
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Jan 18, 2013 | RCV000078342.19 | |
Pathogenic (1) |
no assertion criteria provided
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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. |
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Pathogenic
(Mar 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000790225.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
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Pathogenic
(Jan 18, 2013)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000110188.8
First in ClinVar: Jan 17, 2014 Last updated: Jun 29, 2015 |
Number of individuals with the variant: 7
Sex: mixed
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Pathogenic
(Mar 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
germline
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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:
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)
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Pathogenic
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV004172770.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Mar 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002025005.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: yes
Allele origin:
germline
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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
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Pathogenic
(Jun 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001524522.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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Pathogenic
(Mar 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002781040.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Jan 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001209850.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
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)
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Pathogenic
(Mar 17, 2024)
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criteria provided, single submitter
Method: research
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804931.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
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Pathogenic
(Feb 01, 1998)
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no assertion criteria provided
Method: literature only
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HMG-CoA LYASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000032970.3
First in ClinVar: Apr 04, 2013 Last updated: Mar 18, 2023 |
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)
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Pathogenic
(Aug 25, 2019)
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no assertion criteria provided
Method: clinical testing
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Deficiency of hydroxymethylglutaryl-CoA lyase
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001132938.1
First in ClinVar: Jan 06, 2020 Last updated: Jan 06, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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 |
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Pathogenic
(Oct 13, 2020)
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no assertion criteria provided
Method: clinical testing
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Deficiency of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002094168.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 ...
HelpRecord last updated Apr 20, 2024
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.