ClinVar Miner

Submissions for variant NM_153704.5(TMEM67):c.1645C>T (p.Arg549Cys) (rs747025617)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000636959 SCV000758407 uncertain significance Joubert syndrome; Meckel-Gruber syndrome 2017-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 549 of the TMEM67 protein (p.Arg549Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs747025617, ExAC 0.02%). This variant has been reported to segregate with Meckel syndrome in 1 family (PMID: 26191240). This variant has also been reported as homozygous or in combination with another TMEM67 variant in individuals affected with Meckel syndrome (PMID: 21493627, 23351400). Experimental studies have shown that this missense change is unable to rescue de-regulated Wnt/beta-catenin signaling that is present in a null knockout mouse model (PMID: 26035863). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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