chr5-75359992-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_000859.3(HMGCR):c.2465G>A(p.Gly822Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_000859.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HMGCR | NM_000859.3 | c.2465G>A | p.Gly822Asp | missense_variant | Exon 19 of 20 | ENST00000287936.9 | NP_000850.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Muscular dystrophy, limb-girdle, autosomal recessive 28 Pathogenic:1
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Limb-girdle muscular dystrophy Pathogenic:1
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). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.