ClinVar Genomic variation as it relates to human health
NM_000859.3(HMGCR):c.2465G>A (p.Gly822Asp)
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_000859.3(HMGCR):c.2465G>A (p.Gly822Asp)
Variation ID: 1803007 Accession: VCV001803007.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q13.3 5: 75359992 (GRCh38) [ NCBI UCSC ] 5: 74655817 (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 20, 2023 Jun 24, 2023 Dec 3, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000859.3:c.2465G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000850.1:p.Gly822Asp missense NM_001130996.2:c.2306G>A NP_001124468.1:p.Gly769Asp missense NM_001364187.1:c.2465G>A NP_001351116.1:p.Gly822Asp missense NC_000005.10:g.75359992G>A NC_000005.9:g.74655817G>A NG_011449.1:g.27825G>A - Protein change
- G769D, G822D
- Other names
- NP_000850.1:p.(G822D)
- Canonical SPDI
- NC_000005.10:75359991:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Decreased function
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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.
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- Links
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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HMGCR | - | - |
GRCh38 GRCh37 |
34 | 45 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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 (1) |
criteria provided, single submitter
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Dec 3, 2022 | RCV003232630.2 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 21, 2023 | RCV003228086.3 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Dec 03, 2022)
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criteria provided, single submitter
Method: research
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Limb-girdle muscular dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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The Morris Kahn Laboratory of Human Genetics, Ben-Gurion University of the Negev
Accession: SCV002758004.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
Comment:
Genome-wide linkage analysis, through SNP genotyping for 6 affected individuals and 10 unaffected family members, identified a single 3.2Mbp homozygous segment on chromosome 5q13.2-q13.3, that … (more)
Genome-wide linkage analysis, through SNP genotyping for 6 affected individuals and 10 unaffected family members, identified a single 3.2Mbp homozygous segment on chromosome 5q13.2-q13.3, that was shared among all affected individuals and was either absent or in a heterozygous state in unaffected individuals. The disease-associated locus, spanning between SNPs rs2129403 and rs2914143, 5:73803333-77084175 (GRCh38/hg38), showed a maximal LOD score of 4.8204 at rs4345300. Filtering through whole-exome sequencing data of 2 patients, only a single variant was found within the 3.2 Mbp locus: g.5:75359992G>A (GRCh38/hg38); NM_000859.3 :c.2465G>A; p.(G822D) in HMGCR. The variant is a singleton, is not present in large genomic databases, predicted to be pathogenic according to SIFT and PolyPhen2 algorithms and has a CADD score of 29.6. The homozygous mutated nucleotide, coded amino acid, and the entire gene sequence are highly conserved throughout evolution. The Glycine to Aspartate substitution at position 822 is a radical replacement, predicted to interfere with several peptide bonds, disrupt helix-dipole and cause charge-based repulsion, with possible detrimental impact on secondary and tertiary structure of HMG-CoA reductase. Within the locus, there were no other variants, nor were there any variants in genes known to cause LGMD and LGMD-like diseases throughout the exomes. The HMGCR variant was validated via restriction analysis and Sanger sequencing and was found to fully segregate as expected for autosomal recessive heredity. Of 190 non-related ethnically matched controls of Bedouin tribes other than the one affected, none carried the variant. Screening of 20 individuals of the same tribe did not show other carriers. Functional characterization by spectro-colorimetric analysis of the WT and mutant proteins’ function using an NADPH-oxidation assay demonstrated that, compared to its WT counterpart, the mutant protein had 69% reduction in Vmax and 65% increase in Km in relation to the substrate HMG-CoA, indicating lower affinity of the mutated protein for HMG-CoA, as well as overall slower reaction-rate. This was also supported by ITC analysis of HMG-CoA reductase thermodynamics to a known inhibitor, pravastatin. While the WT protein exhibited a mild exothermic reaction, the mutant form displayed kinetics almost identical to a no-protein control, indicating that the catalytic pocket of the mutant protein has a very low affinity towards pravastatin. To conclude, the HMGCR variant was found to be pathogenic according to ACMG criteria PM2, PP3,PS3, PP4 and PP1 (moderate to strong). (less)
Number of individuals with the variant: 6
Clinical Features:
Hyperglycemia (present) , Elevated circulating aspartate aminotransferase concentration (present) , Muscular atrophy (present) , Weakness of muscles of respiration (present) , Proximal muscle weakness (present) … (more)
Hyperglycemia (present) , Elevated circulating aspartate aminotransferase concentration (present) , Muscular atrophy (present) , Weakness of muscles of respiration (present) , Proximal muscle weakness (present) , Limb muscle weakness (present) , Fatiguable weakness of proximal limb muscles (present) , Exercise-induced myalgia (present) , Reduced tendon reflexes (present) , Elevated circulating creatine kinase concentration (present) , Dysphagia (absent) (less)
Age: 31-60 years
Sex: mixed
Ethnicity/Population group: Arab Bedouin
Geographic origin: Israeli Negev
Method: paired-end 100-bp read protocol at a mean coverage of 100-fold. For exome enrichment, we used SureSelect Human All Exon V6+UTR enrichment kit (Agilent, Santa Clara, CA, USA). Sequencing read alignment, variant calling and annotation were performed by Macrogen (Seoul, Korea) using BWA, GATK and SnpEff, respectively. Data were analyzed using QIAGEN’s Ingenuity Variant Analysis software (www. qiagen.com/ingenuity, QIAGEN, Redwood City, CA, USA). Using the filtering cascade, we excluded variants that were observed in high frequency in normal control samples from open datasets (gnomAD, ExAc, NHLBI ESP, Allele frequency community) as well as in our in-house NGS sequencing database of 450 Bedouin control samples; and included variants that were predicted to have deleterious effect on protein coding sequences, and variants which were experimentally observed to be pathogenic, possibly pathogenic, or have uncertain significance, and filtered for presumed mode-of-inheritance and genes known to cause similar pathological conditions.
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Pathogenic
(Jun 21, 2023)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 28
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV003925057.3
First in ClinVar: May 20, 2023 Last updated: Jun 24, 2023 |
Comment on evidence:
In 6 affected members of a large consanguineous Bedouin kindred with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375), Yogev et al. (2023) identified a homozygous … (more)
In 6 affected members of a large consanguineous Bedouin kindred with autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28; 620375), Yogev et al. (2023) identified a homozygous c.2465G-A transition (c.2465G-A, NM_000859.3) in the HMGCR gene, resulting in a gly822-to-asp (G822D) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in large databases or among 210 ethnically matched controls. In vitro functional studies in SH-SY5Y cells transfected with the mutation showed that the mutant protein had normal subcellular localization, but decreased activity. There was a 69% reduction in V(max) and a 65% increase in K(m) for the HMG-CoA substrate compared to controls. In addition, the catalytic pocket of the mutant protein had a very low affinity for pravastatin. These findings were consistent with a partial loss-of-function effect. The patients had onset of progressive proximal muscle weakness affecting the upper and lower limbs in the fourth decade. Older patients lost ambulation and developed respiratory insufficiency. Mevalonate levels were low in 1 of the patients studied; she showed clinical improvement after treatment with mevalonolactone. (less)
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Decreased function
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The Morris Kahn Laboratory of Human Genetics, Ben-Gurion University of the Negev
Accession: SCV002758004.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone. | Yogev Y | Proceedings of the National Academy of Sciences of the United States of America | 2023 | PMID: 36745799 |
Text-mined citations for this variant ...
HelpRecord last updated Jul 15, 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.