ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.2498T>C (p.Ile833Thr) (rs267607119)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000001446 SCV000256494 pathogenic Joubert syndrome 6 2015-02-23 criteria provided, single submitter research
Invitae RCV000821785 SCV000962554 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 833 of the TMEM67 protein (p.Ile833Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs267607119, ExAC 0.006%). This variant has been observed to segregate with Joubert syndrome in families (PMID: 19058225, 21866095) and has also been observed in individuals with Joubert syndrome (PMID: 19058225, 21866095, 26092869, 28497568, 28973083). ClinVar contains an entry for this variant (Variation ID: 1378). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, Klinikum rechts der Isar RCV000995902 SCV001150294 pathogenic Meckel syndrome, type 3 2018-05-23 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000001446 SCV001164447 likely pathogenic Joubert syndrome 6 2018-12-03 criteria provided, single submitter research The heterozygous p.Ile833Thr variant in TMEM67 was identified by our study in the compound heterozygous state, with a VUS, in one individual with Joubert syndrome. This variant has been reported pathogenic by OMIM in ClinVar (Variation ID: 1378) and has been identified in 0.007909% (10/126438) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs267607119). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Ile833Thr variant in TMEM67 has been reported in 10 individuals from a variety of ethnic backgrounds (Egypt, Croatia, Belgium, Japan, Germany) with Joubert syndrome and segregated with disease in 2 affected relatives from 1 family (PMID: 26092869, 19058225, 21633164, 19508969). The presence of this variant in combination with 4 variants (all reported pathogenic by the literature/OMIM in ClinVar and 1 reported pathogenic in ClinVar by additional submitters) and in 4 individuals with Joubert syndrome increases the likelihood that the p.Ile833Thr variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3_Strong, PP1, PP3 (Richards 2015).
CeGaT Praxis fuer Humangenetik Tuebingen RCV001310635 SCV001500515 pathogenic not provided 2020-12-01 criteria provided, single submitter clinical testing
OMIM RCV000001445 SCV000021595 pathogenic Joubert syndrome with hepatic defect 2011-07-01 no assertion criteria provided literature only
OMIM RCV000001446 SCV000021596 pathogenic Joubert syndrome 6 2011-07-01 no assertion criteria provided literature only

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