ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.308G>A (p.Arg103His) (rs371000425)

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Total submissions: 4
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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 2020-06-22 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, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000800572 SCV000940298 uncertain significance Hypertrophic cardiomyopathy 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 103 of the TNNI3 protein (p.Arg103His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs371000425, ExAC 0.01%). This variant has not been reported in the literature in individuals with TNNI3-related disease. ClinVar contains an entry for this variant (Variation ID: 181577). 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"). 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 Health, Inc RCV001190438 SCV001357931 uncertain significance Cardiomyopathy 2020-12-04 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.

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