Submissions for variant NM_153704.6(TMEM67):c.223+1G>C

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	RCV002510414	SCV002819729	likely pathogenic	Joubert syndrome and related disorders	2022-12-21	criteria provided, single submitter	clinical testing	Variant summary: TMEM67 c.223+1G>C 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 a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251436 control chromosomes. To our knowledge, no occurrence of c.223+1G>C 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 likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003775564	SCV004587350	likely pathogenic	Familial aplasia of the vermis; Meckel-Gruber syndrome	2023-11-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 1 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of TMEM67-related conditions (PMID: 36703223). ClinVar contains an entry for this variant (Variation ID: 1878361). 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.