ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.422G>A (p.Arg141Gln) (rs397516464)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036585 SCV000060240 pathogenic Primary dilated cardiomyopathy 2015-02-02 criteria provided, single submitter clinical testing The p.Arg131Gln variant in TNNT2 has been identified by our laboratory as de nov o in 1 infant and in 1 child with DCM. This variant was absent from large popula tion studies. Additionally, other likely pathogenic amino acid alterations at th is position (p.Arg131Trp and p.Arg131Pro) have been reported, suggesting variati on at this position is not tolerated. Arginine (Arg) at position 131 is highly c onserved in mammals and across evolutionarily distant species and the change to glutamine (Gln) was predicted to be pathogenic using a computational tool clinic ally validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic for DCM in an autosomal dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon multiple de novo occurrences and absence from controls.
GeneDx RCV000520859 SCV000617240 pathogenic not provided 2018-08-10 criteria provided, single submitter clinical testing The R131Q pathogenic variant in the TNNT2 gene has been reported in association with cardiomyopathy (Pugh et al., 2014; Walsh et al., 2017). The R131Q variant results in a semi-conservative amino acid substitution at a position that is conserved across species. Additionally, a variant in the same residue (R131W) and in nearby residues (E128K, R130C, R134W) have been reported in HGMD in association with cardiomyopathy (Stenson et al., 2014), further supporting the functional importance of this residue and this region of the protein. Furthermore, the R131Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).

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