Submissions for variant NM_000257.4(MYH7):c.1640C>A (p.Thr547Asn)

dbSNP: rs876657878

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221870	SCV000272034	uncertain significance	not specified	2015-07-29	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr547Asn variant in MYH7 has not been previously reported in individuals with cardiomyop athy and was absent from large population studies. 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, while there is some suspicion for a pathogenic role, t he clinical significance of the p.Thr547Asn variant is uncertain.
GeneDx	RCV001753646	SCV002007721	uncertain significance	not provided	2020-01-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance; additional evidence is not available (ClinVar Variant ID# 228900; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Invitae	RCV002519641	SCV003330868	uncertain significance	Hypertrophic cardiomyopathy	2022-03-28	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MYH7-related conditions. 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 228900). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 547 of the MYH7 protein (p.Thr547Asn).