Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000423402 | SCV000521218 | likely pathogenic | not provided | 2017-07-21 | criteria provided, single submitter | clinical testing | A published H96R variant that is likely pathogenic has been identified in the TMEM138 gene. The H96R variant has been reported previous in association with Joubert syndrome and related disorders (JSRD) (Lee et al., 2012; Szymanska et al., 2012). Funcational studies suggest that the H96R variant results in an unstable protein (Lee et al., 2012). The H96R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the H96R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. |
| Foundation for Research in Genetics and Endocrinology, |
RCV000024187 | SCV001433669 | likely pathogenic | Joubert syndrome 16 | 2020-09-14 | criteria provided, single submitter | clinical testing | A homozygous missense variation in exon 3 of the TMEM138 gene that results in the amino acid substitution of Arginine for Histidine at codon 96 was detected. The observed variant c.287A>G (p.His96Arg) lies in the transmembrane protein 138 domain of the TMEM138 protein and has previously been reported in patients affected with Joubert syndrome (Lee et al. 2012). The variant is classified as likely pathogenic in ClinVar database. The variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.002% in the gnomAD database. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. |
| Labcorp Genetics |
RCV000024187 | SCV002228732 | pathogenic | Joubert syndrome 16 | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 96 of the TMEM138 protein (p.His96Arg). This variant is present in population databases (rs387907132, gnomAD 0.02%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 22282472). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31188). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TMEM138 function (PMID: 22282472). For these reasons, this variant has been classified as Pathogenic. |
| Revvity Omics, |
RCV000024187 | SCV004238763 | likely pathogenic | Joubert syndrome 16 | 2023-03-14 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000024187 | SCV000045478 | pathogenic | Joubert syndrome 16 | 2012-02-24 | no assertion criteria provided | literature only |