ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.146dup (p.Lys50fs)

gnomAD frequency: 0.00001  dbSNP: rs1162696593
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health 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.
Invitae 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).

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