ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.640A>G (p.Thr214Ala)

dbSNP: rs1468636851
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666652 SCV000790981 uncertain significance Glutaric aciduria, type 1 2017-04-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000666652 SCV002208011 pathogenic Glutaric aciduria, type 1 2022-05-27 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 214 of the GCDH protein (p.Thr214Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 22728054, 24332224). ClinVar contains an entry for this variant (Variation ID: 551561). 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 GCDH protein function. 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.Thr214 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19433437, 30217722). 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.

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