ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4009C>T (p.Arg1337Trp)

gnomAD frequency: 0.00001  dbSNP: rs763326046
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478000 SCV000565292 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The R1337W variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1337W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Although missense variants in nearby residues (R1344Q, R1344W, A1332T, N1327K) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of these variants has not been definitively determined. Nevertheless, observation in additional affected individuals, segregation data, and functional evidence are needed to clarify the pathogenicity of the R1337W variant.
Color Diagnostics, LLC DBA Color Health RCV001524278 SCV001734080 uncertain significance Cardiomyopathy 2023-11-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 1337 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 1/250136 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 RCV003586184 SCV004280019 uncertain significance Hypertrophic cardiomyopathy 2022-12-26 criteria provided, single submitter clinical testing This variant is present in population databases (rs763326046, gnomAD 0.003%). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. ClinVar contains an entry for this variant (Variation ID: 418364). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1337 of the MYH7 protein (p.Arg1337Trp).

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