Submissions for variant NM_000257.4(MYH7):c.4904T>C (p.Met1635Thr)

gnomAD frequency: 0.00004  dbSNP: rs145822086

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158676	SCV000208611	uncertain significance	not provided	2018-02-05	criteria provided, single submitter	clinical testing	p.Met1635Thr (ATG>ACG): c.4904 T>C in exon 34 of the MYH7 gene (NM_000257.2). The M1635T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M1635T variant is observed in 5/24032 (0.02%) alleles from individuals of African background in large population cohorts (Lek et al., 2016). The M1635T 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. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with MYH7-related disorders (Stenson et al., 2014). However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. The variant is found in HCM panel(s).
Invitae	RCV000541040	SCV000623725	uncertain significance	Hypertrophic cardiomyopathy	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1635 of the MYH7 protein (p.Met1635Thr). This variant is present in population databases (rs145822086, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 181269). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH7 protein function with a negative 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.
Color Diagnostics, LLC DBA Color Health	RCV001804876	SCV002052841	uncertain significance	Cardiomyopathy	2022-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1635 of the MYH7 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 5/282844 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.
Ambry Genetics	RCV002336358	SCV002634662	uncertain significance	Cardiovascular phenotype	2021-10-04	criteria provided, single submitter	clinical testing	The p.M1635T variant (also known as c.4904T>C), located in coding exon 32 of the MYH7 gene, results from a T to C substitution at nucleotide position 4904. The methionine at codon 1635 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002484979	SCV002782883	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-10-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001804876	SCV004239474	uncertain significance	Cardiomyopathy	2023-03-06	criteria provided, single submitter	clinical testing