Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV001190032 | SCV001357443 | uncertain significance | Cardiomyopathy | 2023-04-05 | criteria provided, single submitter | clinical testing | This variant inserts 1 nucleotide in exon 4 of the TNNI3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with TNNI3-related disorders in the literature. This variant has been identified in 1/31390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNI3 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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. |
| Ambry Genetics | RCV003293967 | SCV004003349 | uncertain significance | Cardiovascular phenotype | 2023-03-24 | criteria provided, single submitter | clinical testing | The c.146dupT variant, located in coding exon 4 of the TNNI3 gene, results from a duplication of T at nucleotide position 146, causing a translational frameshift with a predicted alternate stop codon (p.K50Efs*60). Although biallelic loss of function alterations in TNNI3 have been associated with autosomal recessive dilated cardiomyopathy, haploinsufficiency for TNNI3 has not been clearly established as a mechanism of disease for autosomal dominant cardiomyopathies. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive dilated cardiomyopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant cardiomyopathies is unclear. |
| Labcorp Genetics |
RCV003770141 | SCV004669680 | pathogenic | Hypertrophic cardiomyopathy | 2023-03-11 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 927030). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Lys50Glufs*60) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TNNI3 are known to be pathogenic (PMID: 35838873, 31568572, 34036930). |
| All of Us Research Program, |
RCV003770141 | SCV004821888 | uncertain significance | Hypertrophic cardiomyopathy | 2023-05-04 | criteria provided, single submitter | clinical testing | Variant of Uncertain Significance due to insufficient evidence: This variant inserts 1 nucleotide in exon 4 of the TNNI3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Disease-causing variants in TNNI3 are mostly missense variants that act in a dominant-negative manner. The role of TNNI3 truncation variants in cardiomyopathy is not clearly established. Available evidence is insufficient to determine the role of this variant in disease conclusively. |