ClinVar Miner

Submissions for variant NM_000432.4(MYL2):c.125G>A (p.Gly42Asp)

gnomAD frequency: 0.00001  dbSNP: rs863225117
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000201445 SCV000256194 likely pathogenic Hypertrophic cardiomyopathy 10 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001178807 SCV001343336 uncertain significance Cardiomyopathy 2018-11-30 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the Ca2+-Mg2+ loop of the EF hand domain 1 of the MYL2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000201445 SCV002280648 uncertain significance Hypertrophic cardiomyopathy 10 2022-12-04 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 217490). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 30297972). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 42 of the MYL2 protein (p.Gly42Asp).
Ambry Genetics RCV002426954 SCV002678325 uncertain significance Cardiovascular phenotype 2022-09-08 criteria provided, single submitter clinical testing The p.G42D variant (also known as c.125G>A), located in coding exon 3 of the MYL2 gene, results from a G to A substitution at nucleotide position 125. The glycine at codon 42 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in two individuals in the Sarcomeric Human Cardiomyopathy Registry (SHaRe) (Ho CY et al. Circulation, 2018 10;138:1387-1398). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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