ClinVar Miner

Submissions for variant NM_153704.5(TMEM67):c.2314_2322+4delinsGG (rs1064792983)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000458928 SCV000552810 pathogenic Joubert syndrome; Meckel-Gruber syndrome 2016-07-02 criteria provided, single submitter clinical testing This variant, c.2314_2322+4delinsGG, is a complex sequence change that deletes 13 nucleotides and inserts 2 nucleotides. This sequence variant spans the exon 22-intron 22 border, and affects the donor splice site in intron 22 of the TMEM67 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in two unborn fetuses from a single family, both diagnosed as "Meckel-like" (PMID: 17160906). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known in the literature as 2315_2323+4del13insGG in the MKS3 gene. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in TMEM67 are known to be pathogenic (PMID: 20232449). In addition, this variant has been observed in trans with a pathogenic variant in individuals affected with TMEM67-related disease. For these reasons, this variant has been classified as Pathogenic.

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