ClinVar Miner

Submissions for variant NM_004752.4(GCM2):c.139C>T (p.Arg47Cys)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV002286021 SCV002575826 likely pathogenic not provided 2022-03-29 criteria provided, single submitter clinical testing Identified along with a second GCM2 variant in an individual with primary hyperparathyroidism (Coppin et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31671402)
Invitae RCV002286021 SCV004515652 pathogenic not provided 2023-05-01 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg47 amino acid residue in GCM2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15863676, 18182452). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 GCM2 protein function. ClinVar contains an entry for this variant (Variation ID: 1707105). This missense change has been observed in individual(s) with GCM2-related conditions (PMID: 31671402; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs200283922, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 47 of the GCM2 protein (p.Arg47Cys).
Molecular Genetics Laboratory, Biocruces Bizkaia Health Research Institute RCV003984247 SCV004708182 uncertain significance Hyperparathyroidism 4 2024-03-08 no assertion criteria provided clinical testing

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