ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.416T>G (p.Phe139Cys)

gnomAD frequency: 0.00001  dbSNP: rs1462112345
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001524283 SCV001734085 uncertain significance Cardiomyopathy 2023-04-05 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with cysteine at codon 139 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 arrhythmogenic cardiomyopathy and in an unaffected family member (PMID: 30385303). This variant has been identified in 3/248810 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.
Invitae RCV001872026 SCV002137783 uncertain significance Hypertrophic cardiomyopathy 2022-07-13 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1171307). This missense change has been observed in individual(s) with TNNI3-related cardiomyopathy (PMID: 30165862, 30385303; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.02%). This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 139 of the TNNI3 protein (p.Phe139Cys).

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