ClinVar Miner

Submissions for variant NM_006790.2(MYOT):c.170C>T (p.Thr57Ile) (rs28937597)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000424803 SCV000331973 pathogenic not provided 2016-07-28 criteria provided, single submitter clinical testing
GeneDx RCV000424803 SCV000515894 pathogenic not provided 2015-04-01 criteria provided, single submitter clinical testing The T57I variant in the MYOT gene has been reported previously in association with autosomal dominantlimb girdle muscular dystrophy in a large North American family (Hauser et al., 2000). Functional studiessuggest that T57I leads to impairment of myotilin degradation, and results in the accumulation of abnormalprotein aggregates in muscle (von Nandelstadh, 2011). Additionally, missense variants (S55F, S60F/C) innearby residues have been reported in the Human Gene Mutation Database in association with MYOT-relateddisorders (Stenson et al., 2014). The T57I substitution is a non-conservative amino acid substitution that alters a residue conserved in mammals. Therefore, the T57I variant is interpreted as pathogenic.
Invitae RCV000639976 SCV000761562 pathogenic Myofibrillar myopathy 3 2020-08-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 57 of the MYOT protein (p.Thr57Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with limb-girdle muscular dystrophy 1A in a large kindred (PMID: 10958653, 3275904). ClinVar contains an entry for this variant (Variation ID: 5834). Experimental studies have shown that this missense change reduces protein degradation and increases protein accumulation in-vitro (PMID: 16801328). Transgenic mouse models of this variant recapitulate the phenotypic features of human myotilinopathies (PMID: 16801328). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000424803 SCV000842842 pathogenic not provided 2018-05-23 criteria provided, single submitter clinical testing
OMIM RCV000639976 SCV000026372 pathogenic Myofibrillar myopathy 3 2000-09-01 no assertion criteria provided literature only
GeneReviews RCV000639976 SCV000055883 pathologic Myofibrillar myopathy 3 2012-10-29 no assertion criteria provided curation Converted during submission to Pathogenic.

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