Submissions for variant NM_024809.5(TCTN2):c.703del (p.Leu235fs)

gnomAD frequency: 0.00002  dbSNP: rs760830696

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000194845	SCV000249142	pathogenic	Meckel syndrome, type 8	2015-02-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000338833	SCV000330632	pathogenic	not provided	2016-07-08	criteria provided, single submitter	clinical testing	The c.703delC pathogenic variant in the TCTN2 gene causes a frameshift starting with codon Leucine 235, changes this amino acid to a Cysteine residue and creates a premature Stop codon at position 52 of the new reading frame, denoted p.L235CfsX52. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this variant has not been previously reported to our knowledge, it is interpreted as a pathogenic variant.
Johns Hopkins Genomics, Johns Hopkins University	RCV001281672	SCV001469016	pathogenic	Joubert syndrome 24	2021-01-13	criteria provided, single submitter	clinical testing	This TCTN2 variant is absent in a large population dataset and has an entry in ClinVar. This 1-bp deletion results in a frameshift in exon 6 of 18 that is predicted to introduce a premature termination codon (PTC), likely leading to nonsense-mediated decay and lack of protein production. This variant alone is not expected to cause Meckel syndrome 8. We consider c.703delC to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509290	SCV002819856	likely pathogenic	Joubert syndrome and related disorders	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: TCTN2 c.703delC (p.Leu235CysfsX52) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in affected individuals (HGMD). The variant was absent in 251488 control chromosomes (gnomAD). To our knowledge, no occurrence of c.703delC in individuals affected with Joubert Syndrome and Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV003765238	SCV004571597	pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-09-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 212389). This variant has not been reported in the literature in individuals affected with TCTN2-related conditions. This variant is present in population databases (rs760830696, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Leu235Cysfs*52) in the TCTN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCTN2 are known to be pathogenic (PMID: 21565611).