ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.281dup (p.Val95fs) (rs780087395)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482021 SCV000566716 pathogenic not provided 2015-06-04 criteria provided, single submitter clinical testing The c.251dupG duplication in the TNNT2 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. The c.251dupG duplication causes a frameshiftstarting with codon Valine 85, changes this amino acid to a Serine residue, and creates a premature Stopcodon at position 4 of the new reading frame, denoted p.Val85SerfsX4. This variant is predicted to causeloss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Thec.251dupG duplication was not observed with any significant frequency in approximately 6500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. We interpret c.251dupG as a pathogenic variant.
Invitae RCV000531928 SCV000646892 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2017-03-27 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 8 of the TNNT2 mRNA (c.251dupG), causing a frameshift at codon 85. This creates a premature translational stop signal (p.Val85Serfs*4) and is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs780087395, ExAC 0.003%) but has not been reported in the literature in individuals with a TNNT2-related disease. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNT2 cause disease. Therefore, this variant has been classified as a Variant of Uncertain Significance.

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