Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001992045 | SCV002284026 | uncertain significance | not provided | 2024-10-27 | 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 491 of the TNNI3K protein (p.Arg491Cys). This variant is present in population databases (rs79936844, gnomAD 0.005%). 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: 1496771). 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. 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. |
| Ambry Genetics | RCV002642021 | SCV003690780 | uncertain significance | Inborn genetic diseases | 2024-11-09 | criteria provided, single submitter | clinical testing | The c.1471C>T (p.R491C) alteration is located in exon 15 (coding exon 15) of the TNNI3K gene. This alteration results from a C to T substitution at nucleotide position 1471, causing the arginine (R) at amino acid position 491 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Genome- |
RCV003348733 | SCV004049426 | uncertain significance | Atrial conduction disease | 2023-04-11 | criteria provided, single submitter | clinical testing | |
| Victorian Clinical Genetics Services, |
RCV003348733 | SCV005086063 | uncertain significance | Atrial conduction disease | 2023-07-16 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with cardiac conduction disease with or without dilated cardiomyopathy (MIM#616117). Loss of function and dominant negative have also been suggested, however the evidence is currently limited (PMIDs: 30010057, 34203974). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. It is also located within a non-canonical splice site region, but without proven consequence on splicing. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2 & v3: 13 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2 & v3) (highest allele count: 4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0600 - Variant is located in the annotated protein tyrosine and serine/threonine kinase domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg491His) has been reported as a VUS by a clinical testing laboratory (ClinVar). No comparable splice site variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS by a clinical testing laboratory (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |