ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.292C>T (p.Arg98Ter) (rs730881068)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159212 SCV000209158 uncertain significance not provided 2016-09-09 criteria provided, single submitter clinical testing The R98X variant in the TNNI3 gene has been reported previously in a 71-year old participant in the Framingham heart study (FHS) who had a normal left ventricular wall thickness and a physiological risk factor for heart disease (Bick et al., 2012). The R98X variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. However, haploinsufficiency is not an established disease mechanism for TNNI3-related cardiomyopathy as the majority of pathogenic variants in TNNI3 are missense changes (Stenson et al., 2014). We interpret R98X as a variant of uncertain significance, which may be related to the cardiomyopathy reported in this individual.
Invitae RCV000628957 SCV000749866 uncertain significance Hypertrophic cardiomyopathy 2020-09-08 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg98*) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs730881068, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in several individuals affected with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 30165862, 28436080, 27532257). ClinVar contains an entry for this variant (Variation ID: 181575). 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170620 SCV001333210 uncertain significance Cardiomyopathy 2018-04-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170620 SCV001357930 uncertain significance Cardiomyopathy 2019-02-16 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000159212 SCV001744119 likely pathogenic not provided no assertion criteria provided clinical testing

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