ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5494C>T (p.Arg1832Cys) (rs201865159)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000626336 SCV000050865 uncertain significance Dilated cardiomyopathy 2018-04-05 criteria provided, single submitter research
Invitae RCV000466702 SCV000546279 uncertain significance Hypertrophic cardiomyopathy 2017-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1832 of the MYH7 protein (p.Arg1832Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201865159, ExAC 0.009%). This variant has been reported in the literature in one individual affected with dilated cardiomyopathy (PMID: 19293840). This variant has been observed in an individual with hypertrophic cardiomyopathy (PMID: 21839045). However, in that individual, a pathogenic allele was also identified in MYBPC3, which suggests that this c.5494C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 161322). 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). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000478825 SCV000565295 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing The R1832C variant of uncertain significance in the MYH7 gene has been reported previously in an adult male with personal and family history of idiopathic dilated cardiomyopathy (Møller et al., 2009). Maron et al. (2012) reported this variant in conjunction with another variant in the MYBPC3 gene, in an adult male with personal and maternal family history of hypertrophic cardiomyopathy. Familial segregation analysis was not performed in either study. The R1832C variant was observed in 7/111,684 (0.006%) alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). R1832C 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. Moreover, 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. Although missense variants in nearby residues (E1829G, S1836L) 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. Thus, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000478825 SCV000609819 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148701 SCV000190430 uncertain significance Primary dilated cardiomyopathy 2014-06-01 no assertion criteria provided research

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