Submissions for variant NM_000257.4(MYH7):c.848A>G (p.Tyr283Cys)

dbSNP: rs727503274

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158769	SCV000208704	likely pathogenic	not provided	2014-06-24	criteria provided, single submitter	clinical testing	The Y283C variant that is likely pathogenic was identified in the MYH7 gene. To our knowledge, this variant has not been published as a mutation or as a benign polymorphism. The Y283C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y283C 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R281T, S291F), have been reported in association with DCM, supporting the functional importance of this region of the protein. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in DCM-CRDM panel(s).
Invitae	RCV001304622	SCV001493913	uncertain significance	Hypertrophic cardiomyopathy	2022-03-23	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 164386). 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. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25611685). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 283 of the MYH7 protein (p.Tyr283Cys).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151306	SCV000199258	uncertain significance	not specified	2014-03-07	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory