ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5533C>T (p.Arg1845Trp)

dbSNP: rs28933098
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000628936 SCV000749844 pathogenic Hypertrophic cardiomyopathy 2024-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1845 of the MYH7 protein (p.Arg1845Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with myosin storage myopathy and skeletal myopathy (PMID: 14520662, 15699387, 17118657, 17336526, 20376763). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14114). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 19336582). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001178343 SCV001342754 uncertain significance Cardiomyopathy 2022-04-08 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 1845 in the LMM domain 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). Functional studies have shown that this variant disrupts myosin filament assembly (PMID: 19336582, 28125727, 28973424) and impairs jump and flight ability in Drosophila mutants (PMID: 28973424, 33234710). This variant has been reported in multiple families and individuals affected with myosin-related disorders without cardiac involvement, including myosin storage myopathy (PMID: 14520662, 15699387, 17118657, 17336526, 20376763), scapulo-peroneal myopathy (PMID: 17336526), hereditary myopathy (PMID: 29170849), and inherited muscle disease (PMID: 31791368). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, while this variant has been reported to cause myosin storage myopathy, the additional evidence is insufficient to determine the role of this variant in cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen RCV001200588 SCV001371589 pathogenic not provided 2021-06-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001200588 SCV002017668 pathogenic not provided 2022-10-26 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV003320033 SCV002579342 likely pathogenic Myosin storage myopathy 2021-10-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017246 SCV004848185 pathogenic Hyaline body myopathy 2020-03-24 criteria provided, single submitter clinical testing The p.Arg1845Trp variant in MYH7 has been reported in at least 10 individuals with myosin storage myopathy and segregated with disease in at least 10 affected family members from at least three families (Tajsharghi 2003, Laing 2005, Shingde 2006, Pegoraro 2007, Kiphuth 2010, Harris 2017, Li 2018). This variant was absent from large population studies, but has been reported in ClinVar (Variation ID: 14114). Computational prediction tools and conservation analyses are consistent with pathogenicity. In vitro and in vivo functional studies support an impact on protein function (Armel 2009, Dahl-Halvarsson 2017, Viswanathan 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant myosin storage myopathy. ACMG/AMP Criteria applied: PP1_Strong, PM2, PS3_Moderate, PS4_Moderate, PP3.
OMIM RCV003320033 SCV000035427 pathogenic Myosin storage myopathy 2009-04-14 no assertion criteria provided literature only

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