ClinVar Miner

Submissions for variant NM_000258.2(MYL3):c.235G>A (p.Val79Ile) (rs150634297)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148716 SCV000190447 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 no assertion criteria provided research
Color RCV000777873 SCV000913880 uncertain significance Cardiomyopathy 2018-05-08 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the EF hand domain of the MYL3 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual with a mild form of late-onset hypertrophic cardiomyopathy (PMID: 22957257). However, three carriers from this family had ECG and/or echocardiographic abnormalities that did not fulfill diagnostic criteria for hypertrophic cardiomyopathy. Also, five carriers from this family showed normal phenotype. This variant has also been identified in 6/246266 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Invitae RCV000527113 SCV000623767 uncertain significance Hypertrophic cardiomyopathy 2018-03-07 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 79 of the MYL3 protein (p.Val79Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs150634297, ExAC 0.01%). This variant has been reported to segregate with a mild form of late-onset hypertrophic cardiomyopathy (PMID: 22957257) . ClinVar contains an entry for this variant (Variation ID: 161329). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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