ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.3235C>T (p.Arg1079Trp) (rs192722540)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000777762 SCV000913728 uncertain significance Cardiomyopathy 2018-10-09 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the neck and hinge (S2 domain) of the MYH7 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. This variant been reported in two individuals with sudden death (PMID: 27707468, 28255936) and an individual affected with dilated cardiomyopathy (PMID: 30165862). This variant has also been identified in 12/246206 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000151250 SCV000530613 uncertain significance not specified 2017-04-14 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The R1079W variant has been reported in one patient with sudden unexplained cardiac death who also harbored another potentially pathogenic variant in the MYH7 gene (Sanchez et al., 2016). The R1079W 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 R1079W 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. This substitution occurs at a position where only amino acids with similar properties to arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, while a missense variant in the same residue (R1079Q) has been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of this variant has not been definitively determined.
Illumina Clinical Services Laboratory,Illumina RCV000365939 SCV000386058 likely benign Myopathy, distal, 1 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000269104 SCV000386059 likely benign Left ventricular noncompaction cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000326571 SCV000386060 likely benign Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000388141 SCV000386061 likely benign Myosin storage myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000277463 SCV000386062 likely benign Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000331325 SCV000386063 likely benign Scapuloperoneal myopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000326571 SCV000623692 uncertain significance Hypertrophic cardiomyopathy 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1079 of the MYH7 protein (p.Arg1079Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs192722540, ExAC 0.07%). This variant has been reported in an individual with sudden unexpected death (PMID: 28704380) and in another individual with sudden unexpected death who also harbored another variant in the MYH7 gene (PMID: 27930701). ClinVar contains an entry for this variant (Variation ID: 164304). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151250 SCV000199151 uncertain significance not specified 2014-06-26 criteria provided, single submitter clinical testing The Arg1079Trp variant in MYH7 has not been reported in individuals with cardiom yopathy but has been detected in 1/200 Chinese chromosomes by the 1000 Genomes P roject (rs192722540). Other variants at this position have been reported (Arg107 9Gly: Girolami 2010, Waldmuller 2011, LMM unpublished data; Arg10479Trp: dbSNP r s192722540), though their significance is unclear. Arginine at position 1079 is not conserved in evolution, though the change to tryptophan (Trp) was predicted to be pathogenic using a computational tool clinically validated by our laborato ry. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, the clinical significance of the Arg1079Trp variant is uncertain.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000627137 SCV000747951 uncertain significance Primary familial hypertrophic cardiomyopathy 2017-06-02 criteria provided, single submitter clinical testing

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