ClinVar Miner

Submissions for variant NM_001276345.2(TNNT2):c.10A>C (p.Ile4Leu)

gnomAD frequency: 0.00004  dbSNP: rs139705141
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523110 SCV000617075 uncertain significance not provided 2020-03-16 criteria provided, single submitter clinical testing Reported in a 41-year-old African American individual without cardiomyopathy in the Jackson Heart Study (Bick et al., 2012); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 449216; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22958901)
Invitae RCV000692553 SCV000820380 uncertain significance Hypertrophic cardiomyopathy 2; Dilated cardiomyopathy 1D; Cardiomyopathy, familial restrictive, 3 2023-12-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the TNNT2 protein (p.Ile4Leu). This variant is present in population databases (rs139705141, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TNNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 449216). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV002448570 SCV002734650 uncertain significance Cardiovascular phenotype 2023-04-25 criteria provided, single submitter clinical testing The p.I4L variant (also known as c.10A>C), located in coding exon 1 of the TNNT2 gene, results from an A to C substitution at nucleotide position 10. The isoleucine at codon 4 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in a population cohort in an individual without apparent cardiomyopathy (Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab RCV003449480 SCV004182103 uncertain significance Dilated cardiomyopathy 1D 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003449481 SCV004182114 uncertain significance Cardiomyopathy, familial restrictive, 3 2023-11-04 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003449479 SCV004182125 uncertain significance Hypertrophic cardiomyopathy 2 2023-11-04 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004003596 SCV004830627 uncertain significance Cardiomyopathy 2024-02-05 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with leucine at codon 4 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TNNT2-related disorders in the literature. This variant has been identified in 3/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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