Submissions for variant NM_000363.5(TNNI3):c.114A>T (p.Lys38Asn)

dbSNP: rs730881066

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159209	SCV000209155	likely pathogenic	not provided	2012-09-12	criteria provided, single submitter	clinical testing	The Lys38Asn variant in the TNNI3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Lys38Asn results in a non-conservative amino acid substitution of positively charged Lysine with a neutral, polar Asparagine at a position that is conserved across species. A mutation in a nearby residue (Lys36Gln) has been reported in association with DCM, supporting the functional importance of this region of the protein. In addition, Carballo et al. note Lys36 is the first of three Lysine residues, including Lys38, and the loss of a positive charge resulted in reduced interaction with the calcium binding site of troponin C. Furthermore, the NHLBI ESP Exome Variant Server reports Lys38Asn was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, the Lys38Asn variant in the TNNI3 gene is likely a mutation, however the possibility it is a rare benign variant cannot be excluded. The variant is found in DCM panel(s).
Color Diagnostics, LLC DBA Color Health	RCV001525777	SCV001735965	uncertain significance	Cardiomyopathy	2020-07-28	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 38 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.
Invitae	RCV001850237	SCV002154953	uncertain significance	Hypertrophic cardiomyopathy	2022-05-18	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 38 of the TNNI3 protein (p.Lys38Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). ClinVar contains an entry for this variant (Variation ID: 181573). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	RCV002453554	SCV002617807	uncertain significance	Cardiovascular phenotype	2021-11-18	criteria provided, single submitter	clinical testing	The p.K38N variant (also known as c.114A>T), located in coding exon 4 of the TNNI3 gene, results from an A to T substitution at nucleotide position 114. The lysine at codon 38 is replaced by asparagine, an amino acid with similar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). This amino acid position is highly 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001525777	SCV003837692	uncertain significance	Cardiomyopathy	2021-10-22	criteria provided, single submitter	clinical testing