Submissions for variant NM_024809.5(TCTN2):c.613G>T (p.Gly205Cys)

dbSNP: rs201827132

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201719	SCV000256479	pathogenic	Familial aplasia of the vermis	2015-02-23	criteria provided, single submitter	research
Invitae	RCV001853239	SCV002313373	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 205 of the TCTN2 protein (p.Gly205Cys). This variant is present in population databases (rs201827132, gnomAD 0.01%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 217702). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TCTN2 protein function with a positive predictive value of 80%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222441	SCV002500714	uncertain significance	not specified	2022-03-28	criteria provided, single submitter	clinical testing	Variant summary: TCTN2 c.613G>T (p.Gly205Cys) results in a non-conservative amino acid change located in the Tectonic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251492 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TCTN2 causing Joubert Syndrome And Related Disorders (5.2e-05 vs 0.0004), allowing no conclusion about variant significance. c.613G>T has been reported in the literature in the compound heterozygous state in an individual affected with Joubert Syndrome (Bachmann-Gagescu_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.