Submissions for variant NM_001082538.3(TCTN1):c.1004_1013delinsCCTCACATACACAGCCTCACATACACAG (p.Asp335_Glu338delinsAlaSerHisThrGlnProHisIleHisArg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002470006	SCV002766132	uncertain significance	not specified	2022-11-10	criteria provided, single submitter	clinical testing	Variant summary: TCTN1 c.1004_1013delins28 (p.Asp335_Glu338delinsAlaSerHisThrGlnProHisIleHisArg) results in an in-frame deletion-insertion in the Tectonic domain (IPR011677) that is predicted to delete 4 amino acids from the protein and replaced them with 10 different amino acids. The variant was absent in 249566 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1004_1013delins28 in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002571442	SCV003461459	uncertain significance	Familial aplasia of the vermis; Meckel-Gruber syndrome	2022-04-07	criteria provided, single submitter	clinical testing	This variant, c.1004_1013delins28, is a complex sequence change that results in the deletion of 4 and insertion of 10 amino acid(s) in the TCTN1 protein (p.Asp335_Glu338delins10). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of TCTN1-related conditions (Invitae). 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 tolerated. 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.