ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.20742T>A (p.Phe6914Leu)

gnomAD frequency: 0.00001  dbSNP: rs397517495
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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, Mass General Brigham Personalized Medicine RCV000039943 SCV000063634 uncertain significance not specified 2013-07-05 criteria provided, single submitter clinical testing The Phe5670Leu variant in TTN has been identified by our laboratory in 1 Caucasi an individual with DCM (LMM unpublished data) and was not identified in large po pulation studies. Phenylalanine (Phe) at position 5670 is not well conserved in evolution and 2 species (chicken and lizard) carry a leucine (Leu; this variant) at this position, suggesting that this change may be tolerated. Other computati onal analyses (biochemical amino acid properties, AlignGVGD, PolyPhen, and SIFT) do not provide strong support for or against an impact to the protein. At this time, additional information is needed to fully assess the clinical significance of the Phe5670Leu variant.
GeneDx RCV000767059 SCV000620706 uncertain significance not provided 2017-09-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TTN gene. The F6597L variant has been reported in one patient with DCM, however, this patient also harbored a nonsense variant in the TTN gene (Pugh et al., 2014). The F5670L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the F5670L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species and where leucine (L) is present as the wild type in at least two species. Finally, this is a missense variant in a gene in which most reported pathogenic variants associated with cardiomyopathy are truncating/loss-of-function (Stenson et al., 2014).

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