Submissions for variant NM_000363.5(TNNI3):c.308G>A (p.Arg103His)

gnomAD frequency: 0.00004  dbSNP: rs371000425

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159214	SCV000209160	uncertain significance	not specified	2014-06-09	criteria provided, single submitter	clinical testing	A variant of unknown significance has been identified in the TNNI3 gene. The R103H variant has not been published as a mutation or reported as a benign polymorphism to our knowledge. The R103H variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, a missense mutation in nearby residue (R98Q) has been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Nevertheless, the R103H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position that is not conserved across species. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Ambry Genetics	RCV000617578	SCV000737137	uncertain significance	Cardiovascular phenotype	2023-04-13	criteria provided, single submitter	clinical testing	The p.R103H variant (also known as c.308G>A), located in coding exon 6 of the TNNI3 gene, results from a G to A substitution at nucleotide position 308. The arginine at codon 103 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in the Framingham and Jackson Heart Study cohorts (Bick AG et al. Am J Hum Genet. 2012;91(3):513-9). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800572	SCV000940298	uncertain significance	Hypertrophic cardiomyopathy	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 103 of the TNNI3 protein (p.Arg103His). This variant is present in population databases (rs371000425, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. ClinVar contains an entry for this variant (Variation ID: 181577). 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 disruptive. 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.
Color Diagnostics, LLC DBA Color Health	RCV001190438	SCV001357931	uncertain significance	Cardiomyopathy	2023-10-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/280856 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.
Revvity Omics, Revvity	RCV003137689	SCV003827698	uncertain significance	not provided	2023-01-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000800572	SCV004819076	uncertain significance	Hypertrophic cardiomyopathy	2024-09-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 8/280856 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003137689	SCV005877761	uncertain significance	not provided	2024-11-21	criteria provided, single submitter	clinical testing	The TNNI3 c.308G>A; p.Arg103His variant (rs371000425, ClinVar Variation ID: 181577) is reported in the literature in two individuals from the Jackson heart study cohort (Bick 2012). This variant is found primarily in the non-Finnish European population with an allele frequency of 0.005% (6/128,628 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.374). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Bick AG et al. Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts. Am J Hum Genet. 2012 Sep 7;91(3):513-9. PMID: 22958901.