Submissions for variant NM_153704.6(TMEM67):c.1132-2A>G

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	RCV002510413	SCV002819728	likely pathogenic	Joubert syndrome and related disorders	2022-12-21	criteria provided, single submitter	clinical testing	Variant summary: TMEM67 c.1132-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the cannonical 3' acceptor site, and two predict the variant creates a 3' acceptor site 6 nucleotides downstream of the wild-type splice site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 249162 control chromosomes. However, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1132-2A>G has been reported in the literature in at least one individual affected with Meckel-Gruber syndrome (e.g. Daum_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003775563	SCV004570806	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-10-10	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 11 of the TMEM67 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 TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This variant is present in population databases (rs777092269, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with TMEM67-related conditions (PMID: 29947050). ClinVar contains an entry for this variant (Variation ID: 1878360). 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.