ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2273G>A (p.Gly758Asp)

gnomAD frequency: 0.00001  dbSNP: rs1163861044
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001177386 SCV001341584 uncertain significance Cardiomyopathy 2023-10-31 criteria provided, single submitter clinical testing This missense variant replaces glycine with aspartic acid at codon 758 of the MYBPC3 protein. Computational prediction tool indicates that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several East Asian individuals affected with hypertrophic cardiomyopathy (PMID: 15563892, 17386157, 21959974, 32492895) and in one individual affected with left ventricular noncompaction (PMID: 28855170). This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV001232370 SCV001404926 pathogenic Hypertrophic cardiomyopathy 2022-09-13 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly758 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 32380161), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 919287). This missense change has been observed in individuals with clinical features of hypertrophic cardiomyopathy or left ventricular noncompaction (PMID: 15563892, 17386157, 21959974, 28855170; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.06%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 758 of the MYBPC3 protein (p.Gly758Asp).
3billion RCV001809988 SCV002058637 uncertain significance Hypertrophic cardiomyopathy 4 2022-01-03 criteria provided, single submitter clinical testing Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MYBPC3 related disorder (PMID:15563892, PS1_P). A different missense change at the same codon has been reported to be associated with MYBPC3 related disorder (PMID:32380161, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.916, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.

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