ClinVar Miner

Submissions for variant NM_153704.5(TMEM67):c.1319G>A (p.Arg440Gln) (rs386834182)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000050177 SCV000807624 uncertain significance Meckel syndrome type 3 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another variant (C78Y) in a fetus with features of Meckel-Gruber syndrome. A second affected fetus from this family was also compound heterozygous for these variants. Heterozygotes are expected to be asymptomatic carriers.
GeneDx RCV000430117 SCV000521233 likely pathogenic not provided 2016-09-02 criteria provided, single submitter clinical testing The R440Q variant in the TMEM67 gene has been reported previously in multiple individuals with Joubert syndrome and related disorders in the homozygous state, as well as in the heterozygous state in the presence of a second TMEM67 variant (Consugar et al., 2007; Khaddour et al., 2007; Brancati et al., 2009; Tallila et al., 2009; Iannicelli et al., 2010; Westerfield et al., 2015; Watson et al., 2016). Additionally, functional and expression studies in mouse models indicate that the R440Q variant impacts the function of the protein (Abdelhamed et al., 2015). The R440Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R440Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. The R440Q variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) RCV000050177 SCV000082587 probable-pathogenic Meckel syndrome type 3 no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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