Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000024186 | SCV002266870 | likely pathogenic | Joubert syndrome 16 | 2022-02-02 | criteria provided, single submitter | clinical testing | 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. 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. ClinVar contains an entry for this variant (Variation ID: 31187). This variant has been observed in individuals with Joubert syndrome and related disorders (PMID: 27081510, 28102635). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change falls in intron 2 of the TMEM138 gene. It does not directly change the encoded amino acid sequence of the TMEM138 protein. It affects a nucleotide within the consensus splice site. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002271376 | SCV002555866 | pathogenic | Joubert syndrome and related disorders | 2022-06-01 | criteria provided, single submitter | clinical testing | Variant summary: TMEM138 c.128+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site, one predicts the variant creates a cryptic 5' donor site, and one predicts the variant weakens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251326 control chromosomes (gnomAD). c.128+5G>A has been reported in the literature in multiple homozygous individuals affected with Joubert Syndrome And Related Disorders (Lee_2012, Bizzari_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV000024186 | SCV000045477 | pathogenic | Joubert syndrome 16 | 2012-02-24 | no assertion criteria provided | literature only |