Submissions for variant NM_000363.5(TNNI3):c.167T>C (p.Ile56Thr)

gnomAD frequency: 0.00001  dbSNP: rs545441942

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000798666	SCV000200737	uncertain significance	Hypertrophic cardiomyopathy	2019-04-05	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not reported in affected people. Seen in one patient at LMM with HCM. Gnomad: 0.01% (3 alleles).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798666	SCV000938292	uncertain significance	Hypertrophic cardiomyopathy	2024-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 56 of the TNNI3 protein (p.Ile56Thr). This variant is present in population databases (rs545441942, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21533915, 27532257, 37652022). ClinVar contains an entry for this variant (Variation ID: 165526). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Fulgent Genetics, Fulgent Genetics	RCV002483314	SCV002785894	uncertain significance	Dilated cardiomyopathy 2A; Cardiomyopathy, familial restrictive, 1; Dilated cardiomyopathy 1FF; Hypertrophic cardiomyopathy 7	2021-09-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162619	SCV003869211	uncertain significance	Cardiovascular phenotype	2022-12-13	criteria provided, single submitter	clinical testing	The p.I56T variant (also known as c.167T>C), located in coding exon 5 of the TNNI3 gene, results from a T to C substitution at nucleotide position 167. The isoleucine at codon 56 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in association with hypertrophic cardiomyopathy (HCM) (van den Wijngaard A et al. Neth Heart J, 2011 Aug;19:344-51; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Tadros R et al. Nat Genet, 2021 Feb;53:128-134). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV004589644	SCV005080272	uncertain significance	not provided	2024-03-13	criteria provided, single submitter	clinical testing	Identified in individuals with HCM in published literature (PMID: 27532257, 21533915); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 21533915)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782258	SCV005394211	uncertain significance	not specified	2024-09-27	criteria provided, single submitter	clinical testing	Variant summary: TNNI3 c.167T>C (p.Ile56Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 233406 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.167T>C has been reported in the literature in individuals affected with Cardiomyopathy (e.g. van den Wijngaard_2011, Walsh_2017, Tadros_2021, McGurk_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37652022, 32278834, 33495596, 27532257, 21533915). ClinVar contains an entry for this variant (Variation ID: 165526). Based on the evidence outlined above, the variant was classified as uncertain significance.