ClinVar Miner

Submissions for variant NM_001077418.3(TMEM231):c.664+4A>G (rs760426025)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000503497 SCV000597500 pathogenic Meckel syndrome, type 11 2016-01-08 criteria provided, single submitter clinical testing
Invitae RCV000650603 SCV000772450 pathogenic Joubert syndrome 20; Meckel syndrome, type 11 2017-12-09 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the TMEM231 gene. It does not directly change the encoded amino acid sequence of the TMEM231 protein, but it affects a nucleotide within the consensus splice site of the intron. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed as homozygous or on the opposite chromosome (in trans) from a pathogenic variant in individuals affected with Meckel syndrome (PMID: 25869670). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 437009). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this change alters splicing leading to premature truncation (PMID: 25869670). For these reasons, this variant has been classified as Pathogenic.

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