Submissions for variant NM_000363.5(TNNI3):c.307C>T (p.Arg103Cys)

gnomAD frequency: 0.00001  dbSNP: rs397516344

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036283	SCV000059935	uncertain significance	not specified	2015-03-16	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Klaassen Lab, Charite University Medicine Berlin	RCV000853159	SCV000995873	uncertain significance	Primary familial hypertrophic cardiomyopathy	2019-07-03	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV001188098	SCV001355066	uncertain significance	Cardiomyopathy	2023-06-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 103 of the TNNI3 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 been reported in two individuals affected with hypertrophic cardiomyopathy (PMID: 31568572, 32815737). One of these individuals also carried a pathogenic variant in the MYH7 gene (PMID:31568572). This variant has also been reported in an individual affected with left ventricular noncompaction (PMID: 28798025). This variant has been identified in 2/280856 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.
Invitae	RCV001852753	SCV002218578	uncertain significance	Hypertrophic cardiomyopathy	2020-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 103 of the TNNI3 protein (p.Arg103Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. 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. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with TNNI3-related conditions (PMID: 28798025, 31568572). ClinVar contains an entry for this variant (Variation ID: 43374). This variant is not present in population databases (ExAC no frequency).
AiLife Diagnostics, AiLife Diagnostics	RCV002223769	SCV002501894	uncertain significance	not provided	2021-08-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002319433	SCV002606873	uncertain significance	Cardiovascular phenotype	2020-06-18	criteria provided, single submitter	clinical testing	The p.R103C variant (also known as c.307C>T), located in coding exon 6 of the TNNI3 gene, results from a C to T substitution at nucleotide position 307. The arginine at codon 103 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in one individual from a left ventricular non-compaction (LVNC) cohort; however clinical details were limited (Miszalski-Jamka K et al. Circ Cardiovasc Genet, 2017 Aug;10:[Epub ahead of print]). 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.