Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000542172 | SCV000634633 | likely pathogenic | Familial aplasia of the vermis; Meckel-Gruber syndrome | 2023-05-29 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with clinical features of Joubert syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs770605718, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 213 of the TMEM67 protein (p.Arg213His). ClinVar contains an entry for this variant (Variation ID: 461772). 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. This variant disrupts the p.Arg213 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been observed in individuals with TMEM67-related conditions (PMID: 17160906), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TMEM67 protein function. |
| Laboratorio de Genetica e Diagnostico Molecular, |
RCV002245001 | SCV002512699 | uncertain significance | Joubert syndrome 6 | 2022-01-19 | criteria provided, single submitter | clinical testing | ACMG classification criteria: PM2 moderate, BP4 supporting |
| Fulgent Genetics, |
RCV002476130 | SCV002791402 | uncertain significance | COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 | 2021-07-06 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003488671 | SCV004242081 | uncertain significance | not specified | 2023-12-08 | criteria provided, single submitter | clinical testing | Variant summary: TMEM67 c.638G>A (p.Arg213His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251344 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.638G>A in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=2), or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. |