Submissions for variant NM_006790.3(MYOT):c.179C>T (p.Ser60Phe)

gnomAD frequency: 0.00001  dbSNP: rs121908458

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725464	SCV000337124	pathogenic	not provided	2016-10-06	criteria provided, single submitter	clinical testing
Invitae	RCV000006194	SCV000638813	pathogenic	Myofibrillar myopathy 3	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 60 of the MYOT protein (p.Ser60Phe). This variant is present in population databases (rs121908458, gnomAD 0.007%). This missense change has been observed in individuals with myofibrillar myopathy (PMID: 15111675, 15947064, 16793270, 19225410, 19590214, 21676617, 25208129, 26842778, 27854214). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5837). 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 disruptive. Experimental studies have shown that this missense change affects MYOT function (PMID: 21361873). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000006194	SCV001150179	pathogenic	Myofibrillar myopathy 3	2019-06-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725464	SCV001248346	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000725464	SCV001817074	likely pathogenic	not provided	2021-03-17	criteria provided, single submitter	clinical testing	Reported previously as a heterozygous change in an individual with onset of symptoms of myofibrillar myopathy at age 77 (Selcen et al., 2004; Functional studies of MYOT constructs encoding S60F failed to exhibit altered myotube dynamics; however, the authors suggested that other aspects of protein function not tested by their assay may be affected (Wang et al., 2011); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32528171, 31589614, 32419263, 32647524, 32509353, 32403337, 31407473, 25208129, 31517061, 19590214, 15111675, 22021208, 27854214)
Revvity Omics, Revvity	RCV000006194	SCV002018188	pathogenic	Myofibrillar myopathy 3	2023-11-13	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000006194	SCV002579900	pathogenic	Myofibrillar myopathy 3	2022-05-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000725464	SCV002770882	pathogenic	not provided	2021-07-28	criteria provided, single submitter	clinical testing	This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and is therefore consistent with pathogenicity. This variant appears to be associated with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging.
PreventionGenetics, part of Exact Sciences	RCV003415664	SCV004115780	pathogenic	MYOT-related disorder	2023-07-27	criteria provided, single submitter	clinical testing	The MYOT c.179C>T variant is predicted to result in the amino acid substitution p.Ser60Phe. This variant has been reported in the heterozygous state in many unrelated individuals with myofibrillar myopathy (Selcen et al. 2004. PubMed ID: 15111675; McNeill et al. 2009. PubMed ID: 19590214; Semmler et al. 2014. PubMed ID: 25208129; Finsterer et al. 2020 PubMed ID: 32509353; Pénisson-Besnier et al. 2006. PubMed ID: 16793270). Additionally, an alternate substitution at this amino acid position (p.Ser60Cys) has been reported as causative in individuals with myofibrillar myopathy (Selcen et al. 2004. PubMed ID: 15111675). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-137206519-C-T). This variant is interpreted as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000006194	SCV004812988	pathogenic	Myofibrillar myopathy 3	2024-02-28	criteria provided, single submitter	clinical testing	Variant summary: MYOT c.179C>T (p.Ser60Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 249028 control chromosomes. c.179C>T has been reported in the literature in multiple individuals affected with dominant late-onset myofibrillar myopathy (e.g. Rudolf_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27854214). ClinVar contains an entry for this variant (Variation ID: 5837). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000006194	SCV000026376	pathogenic	Myofibrillar myopathy 3	2004-04-27	no assertion criteria provided	literature only