ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.258del (p.Leu88fs) (rs727503507)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000152088 SCV000200730 uncertain significance not specified 2019-06-28 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Leu88TrpfsX27 variant in TNNI3 has been reported in 2 individuals with HCM, 1 of whom also carried a suspicious variant in MYH7 (Olivotto 2008). It was also identified in 2/242566 chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 88 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. While heterozygous loss-of-function variants in TNNI3 are uncommon, they have been reported in cases of HCM (Olivotto 2008) and RCM with functional evidence of calcium sensitization (Kaski 2008, Kostareva 2009). However, it remains unclear if the p.Leu88TrpfsX27 variant would impact protein function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Moderate, PM2.
Baylor Genetics RCV001333390 SCV001525951 pathogenic Familial hypertrophic cardiomyopathy 7 2018-11-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV001371359 SCV001567918 uncertain significance Hypertrophic cardiomyopathy 2020-05-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu88Trpfs*27) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs727503507, ExAC 0.002%). This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID:18533079, 25524337). This variant is also known as delC (p.A86fs) in the literature. ClinVar contains an entry for this variant (Variation ID: 165522). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNI3 cause disease. 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.

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