ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.1318C>T (p.Arg440Trp)

gnomAD frequency: 0.00001  dbSNP: rs774746409
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000795737 SCV000935208 pathogenic Familial aplasia of the vermis; Meckel-Gruber syndrome 2024-10-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 440 of the TMEM67 protein (p.Arg440Trp). This variant is present in population databases (rs774746409, gnomAD 0.004%). This missense change has been observed in individual(s) with Joubert syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 642294). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TMEM67 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg440 amino acid residue in TMEM67. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17377820, 17397051, 19058225, 19466712, 20232449). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005047066 SCV005675636 likely pathogenic COACH syndrome 1; Joubert syndrome 6; Meckel syndrome, type 3; RHYNS syndrome; Bardet-Biedl syndrome 14; Nephronophthisis 11 2024-05-06 criteria provided, single submitter clinical testing

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