Submissions for variant NM_001082538.3(TCTN1):c.341+1G>A

gnomAD frequency: 0.00006  dbSNP: rs200241085

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001545104	SCV001764366	likely pathogenic	not provided	2024-05-16	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in an individual with Joubert syndrome who also harbored compound heterozygous variants in the CC2D2A gene (PMID: 25920555); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25920555)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002032552	SCV002266486	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the TCTN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TCTN1 are known to be pathogenic (PMID: 21725307, 22693042, 27894351). This variant is present in population databases (rs200241085, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TCTN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1186116). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471121	SCV002768189	likely pathogenic	Joubert syndrome 13	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 13 (MIM#614173). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (17 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable canonical splice variants in the same intron-exon junction have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic in ClinVar. It has also been reported in a heterozygous state in an individual with Joubert syndrome, however this individual also had 2 likely causative variants in another gene CC2D2A (PMID: 25920555). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign