ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.356C>A (p.Thr119Asn) (rs184709702)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036284 SCV000059936 uncertain significance not specified 2018-02-02 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Ambry Genetics RCV000246112 SCV000320209 uncertain significance Cardiovascular phenotype 2020-09-30 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000036284 SCV000920311 uncertain significance not specified 2018-07-09 criteria provided, single submitter clinical testing 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.
Blueprint Genetics RCV000788296 SCV000927353 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing
Invitae RCV000792760 SCV000932077 uncertain significance Hypertrophic cardiomyopathy 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 119 of the TNNI3 protein (p.Thr119Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs184709702, ExAC 0.02%). This variant has been reported in individuals affected with dilated cardiomyopathy and hypertrophic cardiomyopathy (PMID: 24503780, 25524337, 27532257). ClinVar contains an entry for this variant (Variation ID: 43375). A computational algorithm designed to assess the pathogenicity of variants in TNNI3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be tolerated. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Color Health, Inc RCV001179078 SCV001343667 uncertain significance Cardiomyopathy 2019-08-22 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256760 SCV001433192 uncertain significance Familial hypertrophic cardiomyopathy 1 2020-01-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285210 SCV001471608 uncertain significance none provided 2020-08-23 criteria provided, single submitter clinical testing 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).
Baylor Genetics RCV001333392 SCV001525953 uncertain significance Dilated cardiomyopathy 2A 2018-05-16 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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