ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.562G>A (p.Val188Met) (rs193922409)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159240 SCV000209186 likely pathogenic not provided 2015-12-24 criteria provided, single submitter clinical testing The Val188Met variant in the TNNI3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Val188Met results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. In silico analysis predicts Val188Met is damaging to the protein structure/function. Mutations in nearby residues (Asn185Lys, Arg186Gln, Asp190Gly, Arg192Cys) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Val188Met variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, while Val188Met is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant.The variant is found in HCM panel(s).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000625703 SCV000696596 uncertain significance not specified 2016-10-27 criteria provided, single submitter clinical testing Variant summary: The TNNI3 c.562G>A (p.Val188Met) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this substitution. This variant is absent in 120606 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Mutations in nearby residues (Asn185Lys, Arg186Gln, Glu187Gly, Asp190Gly, Arg192Cys) are listed in HGMD as causative variants for cardiomyopathy or atrial fibrillation indicating the functional importance of this region of the protein. A clinical diagnostic laboratory classified this variant as likely pathogenic (without evidence to independently evaluate). Due to the absence of clinical information about variant carriers and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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