ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.224-2A>T

dbSNP: rs768412278
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002254123 SCV002525406 likely pathogenic not provided 2023-05-31 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Gunay-Aygun et al., 2009); This variant is associated with the following publications: (PMID: 25525159, 19540516)
Labcorp Genetics (formerly Invitae), Labcorp RCV003774755 SCV004592977 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome 2023-06-15 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1691207). Disruption of this splice site has been observed in individual(s) with Joubert syndrome and related disorders (PMID: 19540516). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects an acceptor splice site in intron 1 of the TMEM67 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409).

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