ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.300G>A (p.Met100Ile)

gnomAD frequency: 0.00001  dbSNP: rs759838598
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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 RCV001309614 SCV001499119 pathogenic Glutaric aciduria, type 1 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 100 of the GCDH protein (p.Met100Ile). This variant is present in population databases (rs759838598, gnomAD 0.02%). This missense change has been observed in individual(s) with glutaric acidemia type I (PMID: 34344405). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1011761). 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 not expected to disrupt GCDH protein function with a negative predictive value of 80%. This variant disrupts the p.Met100 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29665094, 34504725). 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.
Natera, Inc. RCV001309614 SCV002086960 uncertain significance Glutaric aciduria, type 1 2020-03-18 no assertion criteria provided clinical testing

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