ClinVar Miner

Submissions for variant NM_000364.4(TNNT2):c.10A>C (p.Ile4Leu) (rs139705141)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523110 SCV000617075 uncertain significance not provided 2017-10-04 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the TNNT2 gene. The I4L variant has been reported in a 41 year-old African American individual without cardiomyopathy in the Jackson Heart Study (Bick et al., 2012), although no family history was described. It has also been observed in one other individual referred HCM genetic testing at GeneDx. Thus far, no segregation data are available for the published case or the case observed at GeneDx to further clarify the role of this variant in disease. The I4L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species and leucine (L) is the wild-type residue at this position in at least two mammalian species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, this variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016).
Invitae RCV000692553 SCV000820380 uncertain significance Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3 2018-04-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 4 of the TNNT2 protein (p.Ile4Leu). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs139705141, ExAC 0.02%). This variant has not been reported in the literature in individuals with TNNT2-related disease. ClinVar contains an entry for this variant (Variation ID: 449216). 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). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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