ClinVar Miner

Submissions for variant NM_000257.3(MYH7):c.4498C>T (p.Arg1500Trp) (rs45544633)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617211 SCV000737223 likely pathogenic Cardiovascular phenotype 2017-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770475 SCV000901918 likely pathogenic Cardiomyopathy 2017-06-12 criteria provided, single submitter clinical testing
Invitae RCV000232679 SCV000284279 pathogenic Hypertrophic cardiomyopathy 2018-05-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1500 of the MYH7 protein (p.Arg1500Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with dilated cardiomyopathy, and there is some evidence suggestive of segregation with disease (PMID: 15556047, 18660445, 19412328, 24119082). ClinVar contains an entry for this variant (Variation ID: 164284). In an experimental study this variant was shown to affect protein stability (PMID: 19854198). Furthermore, a different missense substitution at this codon (p.Arg1500Pro) is known to be deleterious (PMID:15322983, 19854198, 22155079), indicating that the Arg residue is important for MYH7 protein function. 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). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151238 SCV000199112 likely pathogenic Primary dilated cardiomyopathy 2017-08-29 criteria provided, single submitter clinical testing The p.Arg1500Trp variant in MYH7 has been reported in the heterozygous state in 2 adults with LVNC and at least 6 adults with DCM (Kärkkäinen 2004, Jerosch-Herol 2008, Merlo 2013, Hazebroek 2015, ClinVar Variation ID 164284). It was also identified in the homozygous state in 1 child with neonatal DCM (GeneDx personal communication). Furthermore, the variant segregated with disease in 2 affected relatives from 1 family (Jerosch-Herol 2008) and was absent from large population studies. In vitro functional studies provide some evidence that the p.Arg1500Trp variant may impact protein function (Armel 2010, Wolny 2013). However, these types of assays may not accurately represent biological function. Additionally, this variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1500Trp variant is likely pathogenic.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786165 SCV000924859 likely pathogenic not provided 2016-01-11 no assertion criteria provided provider interpretation

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