Submissions for variant NM_000363.5(TNNI3):c.529AAG[1] (p.Lys178del)

dbSNP: rs397516351

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700121	SCV000828863	pathogenic	Hypertrophic cardiomyopathy	2019-11-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant has been observed to be de novo in individuals affected with hypertrophic cardiomyopathy (PMID: 12707239) and restrictive cardiomyopathy (PMID: 21533915). This variant has also been observed in several individuals with hypertrophic cardiomyopathy (PMID: 27532257, 18402758). ClinVar contains an entry for this variant (Variation ID: 43386). This variant is not present in population databases (ExAC no frequency). This variant, c.532_534delAAG, results in the deletion of 1 amino acid of the TNNI3 protein (p.Lys178del), but otherwise preserves the integrity of the reading frame.
Revvity Omics, Revvity	RCV001781349	SCV002022365	pathogenic	not provided	2023-01-02	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001781349	SCV002501406	uncertain significance	not provided	2021-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001781349	SCV002526371	pathogenic	not provided	2023-05-04	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21533915, 27532257, 18402758, 35456187, 12707239, 18403758)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114214	SCV003800738	pathogenic	Cardiomyopathy	2023-01-30	criteria provided, single submitter	clinical testing	Variant summary: TNNI3 c.532_534delAAG (p.Lys178del, aka p.Lys177del) results in an in-frame deletion that is predicted to remove a Lysine amino acid residue from the encoded protein. The variant was absent in 248552 control chromosomes (gnomAD). The variant, c.532_534delAAG has been reported in the literature in individuals affected with hypertrophic and restrictive cardiomyopathy, including at least 2 de novo occurrences (e.g. Richard_2003, Morita_2008, van den Wijngaard_2011, Walsh_2017). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=2) / likely pathogenic (n=1), or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000700121	SCV000059949	pathogenic	Hypertrophic cardiomyopathy	2009-12-02	no assertion criteria provided	clinical testing