ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.755T>C (p.Met252Thr)

gnomAD frequency: 0.00006  dbSNP: rs202149403
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program, University of Washington RCV000001457 SCV000256518 pathogenic Joubert syndrome 6 2015-02-23 criteria provided, single submitter research
GeneDx RCV000418247 SCV000515816 pathogenic not provided 2023-03-08 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17397051, 19466712, 29568536, 20232449, 21866095, 19508969, 26092869, 28497568, 29146704, 23351400, 31589614, 34426522, 36090483, 36788019)
Invitae RCV001389251 SCV001590540 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 252 of the TMEM67 protein (p.Met252Thr). This variant is present in population databases (rs202149403, gnomAD 0.01%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 17397051, 28497568, 29568536). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1387). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TMEM67 function (PMID: 26035863). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000418247 SCV002022348 pathogenic not provided 2021-09-07 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000418247 SCV002564013 pathogenic not provided 2022-07-01 criteria provided, single submitter clinical testing TMEM67: PM3:Very Strong, PM1, PM2
Fulgent Genetics, Fulgent Genetics RCV002490292 SCV002795697 pathogenic COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 2022-05-05 criteria provided, single submitter clinical testing
OMIM RCV000001457 SCV000021607 pathogenic Joubert syndrome 6 2009-10-01 no assertion criteria provided literature only
GeneReviews RCV000234813 SCV000292014 not provided Nephronophthisis no assertion provided literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000418247 SCV001928752 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000418247 SCV001952823 likely pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000418247 SCV001974813 likely pathogenic not provided no assertion criteria provided clinical testing

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