Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001524438 | SCV001734275 | uncertain significance | Cardiomyopathy | 2023-05-03 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with cysteine at codon 74 of the TNNI3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 hypertrophic cardiomyopathy (PMID: 33495597). This variant has been identified in 2/239156 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. |
| Ai |
RCV002224084 | SCV002501876 | uncertain significance | not provided | 2022-01-10 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002424962 | SCV002730802 | uncertain significance | Cardiovascular phenotype | 2019-10-02 | criteria provided, single submitter | clinical testing | The p.R74C variant (also known as c.220C>T), located in coding exon 5 of the TNNI3 gene, results from a C to T substitution at nucleotide position 220. The arginine at codon 74 is replaced by cysteine, an amino acid with highly dissimilar properties. Other variants affecting this codon (p.R74P, p.R74G and p.R74S) have been reported in cardiomyopathy cohorts; however, details were limited (Boda U et al. J. Genet., 2009 Dec;88:373-7; Cecconi M et al. Int. J. Mol. Med., 2016 Oct;38:1111-24; Hayashi T et al. J. Hum. Genet., 2018 Sep;63:989-996). 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. |
| Fulgent Genetics, |
RCV002476835 | SCV002776438 | uncertain significance | Dilated cardiomyopathy 2A; Cardiomyopathy, familial restrictive, 1; Dilated cardiomyopathy 1FF; Hypertrophic cardiomyopathy 7 | 2021-11-08 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV002568781 | SCV003452476 | uncertain significance | Hypertrophic cardiomyopathy | 2022-06-01 | 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 74 of the TNNI3 protein (p.Arg74Cys). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 1171378). 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: "Probably 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. |