Submissions for variant NM_000257.4(MYH7):c.1322C>T (p.Thr441Met)

gnomAD frequency: 0.00006  dbSNP: rs121913653

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000777877	SCV001842665	benign	Cardiomyopathy	2021-06-16	reviewed by expert panel	curation	The c.1322C>T (p.Thr441Met) in MYH7 has been identified in 0.2% (FAF 95% CI; 47/18394) of East Asian chromosomes in gnomAD (BA1; https://gnomad.broadinstitute.org). While this variant lies in the head region of the protein (aa 181-937), where missense variants are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257), this is not considered to be in conflict with BA1 since benign variation within this region was considered during that analysis. In summary, this variant meets criteria to be classified as benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BA1, PM1.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035714	SCV000059365	likely benign	not specified	2017-08-30	criteria provided, single submitter	clinical testing	MYH7 1322C>T: Disclaimer: This variant has not undergone a full assessment. The following are preliminary notes: Classified as VUS3 in 2014 and no new pubs sin ce then. Has a max MAF in ExAC of 0.15% (13 alleles) and gnomad of 0.27% (53 al leles) - frequency too high for disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087154	SCV000218781	likely benign	Hypertrophic cardiomyopathy	2023-12-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000767122	SCV000617059	uncertain significance	not provided	2016-02-12	criteria provided, single submitter	clinical testing	The T441M variant in the MYH7 gene has been reported previously in one child with skeletal myopathy with mild atrial enlargement and septal thickness in the 95th percentile and was absent in 200 control chromosomes (Darin et al., 2007). Expression studies showed that mutated and wild-type alleles were equally expressed at the mRNA level (Darin et al., 2007). The T441M variant has also been reported in one Chinese family with hypertrophic cardiomyopathy (Fan et al., 2011; Feng et al., 2011). The T441M variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. The T441M 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. However, this substitution occurs at a position in the myosin motor domain that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (N437D, M439T, M439R, V440M, R442C, R442H, I443T, N444S) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret T441M as a variant of uncertain significance, which may be related to the muscle weakness and atrophy reported in this individual.
Color Diagnostics, LLC DBA Color Health	RCV000777877	SCV000913885	likely benign	Cardiomyopathy	2018-10-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000989191	SCV001139416	benign	Hypertrophic cardiomyopathy 1	2023-08-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496367	SCV002798635	likely benign	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-11-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000767122	SCV003817728	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777877	SCV004239434	likely benign	Cardiomyopathy	2023-01-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000777877	SCV004818535	likely benign	Cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing
OMIM	RCV000192200	SCV000035437	pathogenic	MYH7-related skeletal myopathy	2007-06-05	no assertion criteria provided	literature only