ClinVar Miner

Submissions for variant NM_153704.5(TMEM67):c.1115C>A (p.Thr372Lys) (rs863225235)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000763608 SCV000894454 pathogenic COACH syndrome; Joubert syndrome 6; Meckel syndrome type 3; Bardet-Biedl syndrome 14; Nephronophthisis 11 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000419395 SCV000521232 likely pathogenic not provided 2016-09-29 criteria provided, single submitter clinical testing The T372K variant in the TMEM67 gene has been reported previously in multiple individuals with Joubert syndrome and related disorders in the homozygous state, as well as in the heterozygous state in the presence of a second TMEM67 variant (Brancati et al., 2009; Doherty et al., 2010; Iannicelli et al., 2010). The T372K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T372K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. The T372K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000636949 SCV000758397 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 372 of the TMEM67 protein (p.Thr372Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous and/or in combination with another TMEM67 variant in several individuals affected with Joubert syndrome (PMID: 26092869, 20232449, 19574260, 25920555). In addition, it has also been reported to segregate with with another TMEM67 variant and in a family affected with Joubert syndrome (PMID: 19058225, 12368986). ClinVar contains an entry for this variant (Variation ID: 217726). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
UW Hindbrain Malformation Research Program,University of Washington RCV000201528 SCV000256520 pathogenic Joubert syndrome 6 2015-02-23 criteria provided, single submitter research

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