Submissions for variant NM_000363.5(TNNI3):c.293G>A (p.Arg98Gln)

gnomAD frequency: 0.00004  dbSNP: rs747522089

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523164	SCV000617287	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TNNI3 gene. The R98Q variant has been published in association with HCM (Rani et al., 2012). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R98Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position where amino acids with similar properties to arginine (R) are tolerated across species. Finally, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Color Diagnostics, LLC DBA Color Health	RCV000772060	SCV000905088	uncertain significance	Cardiomyopathy	2022-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 98 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 been reported in an individual affected with severe obstructive hypertrophic cardiomyopathy and family history of sudden cardiac death (PMID: 22876777). This variant has been identified in 6/280814 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	RCV001851483	SCV002200677	uncertain significance	Hypertrophic cardiomyopathy	2023-07-24	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 449314). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 22876777). This variant is present in population databases (rs747522089, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 98 of the TNNI3 protein (p.Arg98Gln).
Ambry Genetics	RCV003302755	SCV003990499	uncertain significance	Cardiovascular phenotype	2023-06-04	criteria provided, single submitter	clinical testing	The p.R98Q variant (also known as c.293G>A), located in coding exon 6 of the TNNI3 gene, results from a G to A substitution at nucleotide position 293. The arginine at codon 98 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in an individual with hypertrophic obstructive cardiomyopathy (Rani DS et al. BMC Med Genet, 2012 Aug;13:69). This amino acid position is 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.