ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5458C>T (p.Arg1820Trp) (rs145734640)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158703 SCV000208638 likely pathogenic not provided 2014-02-20 criteria provided, single submitter clinical testing p.Arg1820Trp (CGG>TGG): c.5458 C>T in exon 37 of the MYH7 gene (NM_000257.2). The Arg1820Trp variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg1820Trp results in a non-conservative amino acid substitution of positively charged Arginine residue with a non-polar Tryptophan residue at a position that is conserved in mammals. In silico analysis predicts Arg1820Trp is probably damaging to the protein structure/function. Mutations in nearby residues (Glu1829Gly, Arg1832Cys) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. The Arg1820Trp variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project.In summary, while Arg1820Trp is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM-CRDM panel(s).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000158703 SCV000344616 uncertain significance not provided 2016-08-18 criteria provided, single submitter clinical testing
Invitae RCV000685507 SCV000812990 uncertain significance Hypertrophic cardiomyopathy 2018-02-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1820 of the MYH7 protein (p.Arg1820Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs145734640, ExAC 0.01%). This variant has been reported as homozygous in two siblings affected with myosin storage myopathy in combination with cardiac dysfunction and/or dilated cardiomyopathy (PMID: 25666907). ClinVar contains an entry for this variant (Variation ID: 181282). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). However, this prediction has not been confirmed by published functional studies and its 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.
OMIM RCV000172878 SCV000223868 pathogenic Myopathy, myosin storage, autosomal recessive 2015-04-01 no assertion criteria provided literature only

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