Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002509688 | SCV002819546 | pathogenic | Joubert syndrome and related disorders | 2022-12-14 | criteria provided, single submitter | clinical testing | Variant summary: TMEM67 c.2439G>A (p.Ala813Ala) alters a conserved nucleotide located close to 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: three predict the variant abolishes a 5' splicing donor site, and one predicts the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 250872 control chromosomes. c.2439G>A has been reported in the literature in individuals affected with Joubert Syndrome and related disorders, namely Meckel Syndrome, and was shown to segregate with disease within families (e.g. Khaddour_2007, Shaheen_2015, Liu_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Labcorp Genetics |
RCV002538533 | SCV003277814 | pathogenic | Familial aplasia of the vermis; Meckel-Gruber syndrome | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change affects codon 813 of the TMEM67 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TMEM67 protein. This variant also falls at the last nucleotide of exon 23, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201791586, gnomAD 0.007%). This variant has been observed in individual(s) with TMEM67-related conditions (PMID: 17397051, 26123494). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1252093). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Genomic Medicine Center of Excellence, |
RCV001844407 | SCV001870530 | pathogenic | Meckel syndrome, type 3 | 2021-04-29 | no assertion criteria provided | research |