Submissions for variant NM_000257.4(MYH7):c.4762C>T (p.Arg1588Cys)

gnomAD frequency: 0.00002  dbSNP: rs1194197356

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001213343	SCV001384969	uncertain significance	Hypertrophic cardiomyopathy	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1588 of the MYH7 protein (p.Arg1588Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MYH7-related conditions (PMID: 34503678). ClinVar contains an entry for this variant (Variation ID: 943200). 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%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797828	SCV002041521	uncertain significance	not specified	2021-11-29	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.4762C>T (p.Arg1588Cys) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251474 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4762C>T has been observed in one individual affected with nonsyndromic congenital heart disease (echo diagnosis: ventricular septal defect) (Ekure_2021). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001806051	SCV002052879	uncertain significance	Cardiomyopathy	2023-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1588 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual who was affected with non-syndromic congenital heart disease (PMID: 33448881). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001806051	SCV004836206	uncertain significance	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 1588 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual who was affected with non-syndromic congenital heart disease (PMID: 33448881). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.