ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.5C>T (p.Ala2Val) (rs397516359)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000036309 SCV000059961 uncertain significance not specified 2019-06-28 criteria provided, single submitter clinical testing The p.Ala2Val variant in TNNI3 has been reported as homozygous in 2 individuals with DCM and segregated in the homozygous state in 1 affected sibling (Murphy 2004, LMM data). In vitro functional studies provide some evidence that the p.Ala2Val variant may impact protein function (Murphy 2004, Henze 2013). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. This variant has been identified in 0.03% (8/30592) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency raises the possibility that the variant does not cause disease in the heterozygous state but is not inconsistent with a recessive mode of inheritance. In summary, due to conflicting evidence, the clinical significance of the p.Ala2Val variant is uncertain. ACMG/AMP Criteria applied: PP1, PM3_Supporting, PS3_Supporing, BS1_Supporting, BP4.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769534 SCV000900929 uncertain significance Cardiomyopathy 2016-11-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000769534 SCV001360401 uncertain significance Cardiomyopathy 2020-03-24 criteria provided, single submitter clinical testing
OMIM RCV000013240 SCV000033487 pathogenic Dilated cardiomyopathy 2A 2009-08-14 no assertion criteria provided literature only

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