ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.544G>T (p.Ala182Ser) (rs730881097)

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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 RCV000615596 SCV000710841 likely pathogenic Primary dilated cardiomyopathy 2016-04-28 criteria provided, single submitter clinical testing The p.Ala172Ser variant in TNNT2 has been reported in 1 individual with DCM and segregated with disease in at least 4 affected relatives (Stefanelli 2004). It w as absent from large population studies. This variant was predicted to be pathog enic using a computational tool clinically validated by our laboratory. This too l's pathogenic prediction is estimated to be correct 94% of the time (Jordan 201 1). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000778960 SCV000915387 uncertain significance Left ventricular noncompaction 6 2017-10-12 criteria provided, single submitter clinical testing The TNNT2 c.514G>T (p.Ala172Ser) missense variant (which has also been referred to as p.Ala171Ser) has been reported in two studies in which it was identified in a heterozygous state in at least nine clinically affected members of a large, multigenerational family affected by left ventricular dilatation, systolic dysfunction, and sudden cardiac death (Stefanelli et al. 2004). The p.Ala172Ser variant was also detected in an unrelated individual with dilated cardiomyopathy (Jáchymová et al. 2012). Three clinically indeterminate and three asymptomatic members of the large family also carried the variant. Within the family, male carriers of the variant had more severe symptoms, and two of them died suddenly (Stefanelli et al. 2004). The p.Ala172Ser variant was absent from 212 control individuals and is reported at a frequency of 0.000024 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies of the variant have not been conducted, but it affects a highly conserved residue in the alpha-tropomyosin binding domain (Stefanelli et al. 2004). Based on the limited evidence available, the p.Ala172Ser variant is classified as a variant of unknown significance but suspicious for pathogenicity for autosomal dominant dilated cardiomyopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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