ClinVar Genomic variation as it relates to human health

The TNNI3 c.356C>A; p.Thr119Asn variant (rs184709702) is reported in the literature in cohort studies of patients affected with dilated and hypertrophic cardiomyopathies (Walsh 2017 and Coppini 2014). This variant is also reported to the ClinVar database as uncertain (Variation ID: 43375). It is also found in the general population with an overall allele frequency of 0.003% (10/280,786 alleles) in the Genome Aggregation Database. The threonine at codon 119 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Thr119Asn variant is uncertain at this time. References: Coppini et al. Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. J Am Coll Cardiol. 2014 Dec 23. Walsh et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb. Gene statement: Pathogenic variants in TNNI3 are associated with autosomal dominant hypertrophic cardiomyopathy 7 (MIM: 613690), familial restrictive cardiomyopathy 1 (MIM: 115210), dilated cardiomyopathy 1FF (MIM: 613286), and autosomal recessive dilated cardiomyopathy 2A (MIM: 611880).

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

The p.T119N variant (also known as c.356C>A), located in coding exon 6 of the TNNI3 gene, results from a C to A substitution at nucleotide position 356. The threonine at codon 119 is replaced by asparagine, an amino acid with similar properties. This variant was observed in one individual reported to have hypertrophic cardiomyopathy (HCM); however, clinical details were limited (Coppini R et al. J Am Coll Cardiol. 2014;64(24):2589-600). This variant was also reported in two individuals with dilated cardiomyopathy (DCM) who also had variants in other cardiac related genes (Pugh TJ et al. Genet Med. 2014;16(8):601-8). This amino acid position is not well conserved in available vertebrate species, and asparagine is the reference amino acid in other 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.

Variant summary: TNNI3 c.356C>A (p.Thr119Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 277112 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.356C>A, has been reported in the literature in individuals affected with Cardiomyopathy (Walsh_2016, Pugh_2014, Coppini_2014, Lakdawala_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been reported in our internal database (MYH7 c.2722C>G, p.Leu908Val) providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

Reported in individuals with DCM and HCM referred for genetic testing at GeneDx and in published literature (Lakdawala et al., 2012; Coppini et al., 2014; Pugh et al., 2014; Wang et al., 2016; Walsh et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26169204, 27532257, 24503780, 26440512, 22464770, 25524337)

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 119 of the TNNI3 protein (p.Thr119Asn). This variant is present in population databases (rs184709702, gnomAD 0.01%). This missense change has been observed in individual(s) with dilated cardiomyopathy and hypertrophic cardiomyopathy (PMID: 24503780, 25524337, 27532257). ClinVar contains an entry for this variant (Variation ID: 43375). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine 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.

Criteria: PM2, PP2, BP4

This missense variant replaces threonine with asparagine at codon 119 of the TNNI3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 25524337). This variant has been identified in 10/280786 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.

The p.Thr119Asn variant in TNNI3 has been reported in 2 individuals with DCM and 1 individual with HCM (Coppini 2014, LMM data), but has been identified in 3/24022 of African and 3/126650 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs184709702). Computational prediction tools and conservation analysis suggest that the p.Thr119Asn variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Thr119Asn variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting; BP4.

This missense variant replaces threonine with asparagine at codon 119 of the TNNI3 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 25524337, 30297972) and in two individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257). This variant has been identified in 10/280786 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.