ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs121913653
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Total submissions: 11
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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; 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.
Invitae 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

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