ClinVar Miner

Submissions for variant NM_153704.6(TMEM67):c.1338T>G (p.Asp446Glu)

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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 RCV002579864 SCV002934558 uncertain significance Familial aplasia of the vermis; Meckel-Gruber syndrome 2022-06-30 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMEM67 protein function. This variant has not been reported in the literature in individuals affected with TMEM67-related conditions. This variant is present in population databases (rs764380675, gnomAD 0.004%). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 446 of the TMEM67 protein (p.Asp446Glu).
PreventionGenetics, part of Exact Sciences RCV004534121 SCV004114420 likely pathogenic TMEM67-related disorder 2022-10-14 criteria provided, single submitter clinical testing The TMEM67 c.1338T>G variant is predicted to result in the amino acid substitution p.Asp446Glu. To our knowledge, this variant has not been reported in the literature. This variant has been observed in 2 out of ~282,000 alleles in the gnomAD database (http://gnomad.broadinstitute.org/variant/8-94798500-T-G). A different substitution affecting the same amino acid (p.Asp446His) was reported in association with Meckel-Gruber syndrome (Khaddour et al. 2007. PubMed ID: 17397051). The c.1338T>G (p.Asp446Glu) variant was previously detected in trans with a pathogenic variant in a patient tested for Joubert and Meckel-Gruber syndromes at PreventionGenetics. Taken together we classify the c.1338T>G (p.Asp446Glu) variant as likely pathogenic.

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