Submissions for variant NM_006790.3(MYOT):c.1294A>T (p.Thr432Ser)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003079407	SCV003462596	uncertain significance	Myofibrillar myopathy 3	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 432 of the MYOT protein (p.Thr432Ser). This variant is present in population databases (rs200619317, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MYOT-related conditions. ClinVar contains an entry for this variant (Variation ID: 2152659). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Revvity Omics, Revvity	RCV003079407	SCV003810956	uncertain significance	Myofibrillar myopathy 3	2019-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV003134623	SCV003837345	uncertain significance	not provided	2022-08-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22349301)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317646	SCV004021059	uncertain significance	not specified	2023-06-26	criteria provided, single submitter	clinical testing	Variant summary: MYOT c.1294A>T (p.Thr432Ser) results in a conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 (i.e., 3 heterozygotes) in 251394 control chromosomes (gnomAD v2.1, Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1294A>T in individuals affected with Spheroid Body Myopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.