ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.1975C>T (p.Arg659Ter)

gnomAD frequency: 0.00004  dbSNP: rs150332116
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001384718 SCV001584339 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome 2024-01-24 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg659*) in the TMEM67 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM67 are known to be pathogenic (PMID: 20232449, 23559409). This variant is present in population databases (rs150332116, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with TMEM67-related conditions. ClinVar contains an entry for this variant (Variation ID: 1072098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002499801 SCV002805854 pathogenic COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 2021-09-01 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003132490 SCV003814093 likely pathogenic not provided 2021-11-30 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004531194 SCV004113433 likely pathogenic TMEM67-related disorder 2023-04-07 criteria provided, single submitter clinical testing The TMEM67 c.1975C>T variant is predicted to result in premature protein termination (p.Arg659*). This variant was reported in the compound heterozygous state in individuals with Meckel syndrome, Joubert syndrome, and CNS anomaly phenotypes (Stembalska et al 2021. PubMed ID: 34356094; Table S1 - Sukenik-Halevy et al 2022. PubMed ID: 35032046; Yaron et al 2022. PubMed ID: 35229910). This variant is reported in 0.12% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-94809573-C-T). Nonsense variants in TMEM67 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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