ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.422G>C (p.Arg141Pro) (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 RCV000036586 SCV000060241 likely pathogenic Primary dilated cardiomyopathy 2012-12-11 criteria provided, single submitter clinical testing The Arg131Pro variant in TNNT2 has not been reported in the literature nor previ ously identified by our laboratory. This variant has also not been identified in large and broad European American and African American populations by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS); this low frequency is consistent with a disease causing role but insufficient to establish this wi th confidence. Arginine (Arg) at position 131 is highly conserved in mammals and across evolutionarily distant species and the change to Proline (Pro) was predi cted to be pathogenic using a computational tool clinically validated by our lab oratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In addition, two other variants at this position (Arg131Trp , Arg131Gln) have been reported as de novo changes in DCM and LVNC probands, sug gesting that a change to this position may not be tolerated (LMM unpublished dat a, Mogensen 2004, Klaasen 2008). In summary, this variant is likely to be pathog enic, though additional studies are required to fully establish its clinical sig nificance.
Invitae RCV000534598 SCV000646898 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2017-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 131 of the TNNT2 protein (p.Arg131Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a TNNT2-related disease. ClinVar contains an entry for this variant (Variation ID: 43638). A computational algorithm designed to assess the pathogenicity of variants in TNNT2 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). A different missense substitution at this codon (p.Arg131Trp) has been determined to be pathogenic (PMID: 15542288, 15923195, 17932326, 18506004, 24503780, 21551322, 22675533, 24119082). This suggests that the arginine residue is critical for TNNT2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant has uncertain impact on TNNT2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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