Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002002129 | SCV002215069 | uncertain significance | Familial aplasia of the vermis; Meckel-Gruber syndrome | 2022-08-05 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 214 of the TMEM67 protein (p.Tyr214Cys). This variant is present in population databases (rs768183184, gnomAD 0.004%). This missense change has been observed in individual(s) with TMEM67-related conditions (PMID: 28680603). ClinVar contains an entry for this variant (Variation ID: 1436512). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Fulgent Genetics, |
RCV002503668 | SCV002798323 | uncertain significance | COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 | 2024-02-09 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004587261 | SCV005076643 | uncertain significance | not specified | 2024-04-23 | criteria provided, single submitter | clinical testing | Variant summary: TMEM67 c.641A>G (p.Tyr214Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251338 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.641A>G has been reported in the literature in the compound heterozygous state in an individual affected with congenital hepatic fibrosis, but no additional signs of MeckelGruber or Joubert syndrome (Vogel_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28680603). ClinVar contains an entry for this variant (Variation ID: 1436512). Based on the evidence outlined above, the variant was classified as uncertain significance. |