Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000823807 | SCV000964677 | likely pathogenic | Familial aplasia of the vermis; Meckel-Gruber syndrome | 2022-03-22 | 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. This variant disrupts the p. Arg441 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19574260, 23351400). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function. ClinVar contains an entry for this variant (Variation ID: 56765). This missense change has been observed in individual(s) with Meckel-Gruber syndrome (PMID: 20232449). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 441 of the TMEM67 protein (p.Arg441Leu). |
| Juha Muilu Group; Institute for Molecular Medicine Finland |
RCV000050178 | SCV000082588 | probable-pathogenic | Meckel syndrome, type 3 | no assertion criteria provided | not provided | Converted during submission to Likely pathogenic. |