Submissions for variant NM_002471.4(MYH6):c.3758C>T (p.Thr1253Met)

gnomAD frequency: 0.00001  dbSNP: rs201051663

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151216	SCV000199059	uncertain significance	not specified	2014-10-22	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Thr1253Met va riant in MHY6 has not been previously reported in individuals with cardiomyopath y or in large population studies. Threonine (Thr) at position 1253 is not conser ved in mammals or in evolutionarily distant species and 2 mammals (macaque and m anatee) have a methionine (Met) at this position, suggesting that this change ma y be tolerated. Additional computational prediction tools suggest that the p.Thr 1253Met variant may impact the protein, though this information is not predictiv e enough to determine pathogenicity. In summary, while the clinical significance of the p.Thr1253Met variant is uncertain, the presence of the variant amino aci d in other mammals suggests that it is more likely to be benign.
GeneDx	RCV000766423	SCV000569467	uncertain significance	not provided	2017-02-02	criteria provided, single submitter	clinical testing	The T1253M variant in the MYH6 gene has been reported previously in an individual with sporadic dilated cardiomyopathy (Zhao et al., 2015). The T1253M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T1253M 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. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T1253M as a variant of uncertain significance.
Ambry Genetics	RCV002345467	SCV002623016	uncertain significance	Cardiovascular phenotype	2024-10-30	criteria provided, single submitter	clinical testing	The p.T1253M variant (also known as c.3758C>T), located in coding exon 25 of the MYH6 gene, results from a C to T substitution at nucleotide position 3758. The threonine at codon 1253 is replaced by methionine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002505149	SCV002816777	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-09-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544354	SCV004787446	uncertain significance	MYH6-related disorder	2023-12-26	no assertion criteria provided	clinical testing	The MYH6 c.3758C>T variant is predicted to result in the amino acid substitution p.Thr1253Met. This variant was reported in an individual with dilated cardiomyopathy (Zhao et al. 2015. PubMed ID: 26458567) and an individual with left ventricular noncompaction (Table S2, Mazzarotto et al. 2021. PubMed ID: 33500567). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD and has been interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/164229/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.