Submissions for variant NM_015978.3(TNNI3K):c.187C>T (p.Arg63Cys)

gnomAD frequency: 0.00001  dbSNP: rs79045456

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001355907	SCV002269731	uncertain significance	not provided	2024-09-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 63 of the TNNI3K protein (p.Arg63Cys). This variant is present in population databases (rs79045456, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TNNI3K-related conditions. ClinVar contains an entry for this variant (Variation ID: 1049591). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TNNI3K protein function with a negative predictive value of 80%. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355907	SCV001550925	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TNNI3K p.R63C variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs79045456) and in control databases in 8 of 282308 chromosomes at a frequency of 0.00002834, and was observed at the highest frequency in the East Asian population in 6 of 19924 chromosomes (freq: 0.0003011) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.R63 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Center for Computational Biology & Bioinformatics, University of California, San Diego	RCV004570863	SCV005050094	uncertain significance	Meniere disease	2024-06-03	no assertion criteria provided	research