Submissions for variant NM_000257.4(MYH7):c.530C>T (p.Thr177Ile)

gnomAD frequency: 0.00001  dbSNP: rs752930302

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168838	SCV000539840	uncertain significance	not specified	2017-03-01	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 3 papers HGMD, variant found in 1 patient with a TNNT2 variant, 1 variant in 1 HCM cohort,
Invitae	RCV000471746	SCV000546251	uncertain significance	Hypertrophic cardiomyopathy	2022-03-07	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 177 of the MYH7 protein (p.Thr177Ile). This variant is present in population databases (rs752930302, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 27247418). ClinVar contains an entry for this variant (Variation ID: 188596). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV001178571	SCV001343042	uncertain significance	Cardiomyopathy	2023-08-04	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 177 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 23140321, 27247418). One of these individuals also carried a pathogenic variant in the TNNT2 gene (PMID: 20624503). This variant has been identified in 3/251482 chromosomes 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.
MGZ Medical Genetics Center	RCV002288776	SCV002580838	uncertain significance	Hypertrophic cardiomyopathy 1	2022-02-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345564	SCV002643108	uncertain significance	Cardiovascular phenotype	2020-05-15	criteria provided, single submitter	clinical testing	The p.T177I variant (also known as c.530C>T), located in coding exon 4 of the MYH7 gene, results from a C to T substitution at nucleotide position 530. The amino acid change results in threonine to isoleucine at codon 177, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts; however, in one case, it co-occurred with a mutation in the TNNT2 gene (Millat G et al. Eur J Med Genet. 2010 Jul;53:261-7; Teirlinck CH et al. BMC Med. Genet., 2012 Nov;13:105; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6). A different variant affecting this codon (p.T177S, c.530C>G) has been detected in an HCM cohort; however, it co-occurred with another variant in a cardiac-related gene (Mademont-Soler I et al. PLoS ONE, 2017 Aug;12:e0181465). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001178571	SCV003838116	uncertain significance	Cardiomyopathy	2022-02-16	criteria provided, single submitter	clinical testing