ClinVar Miner

Submissions for variant NM_000159.4(GCDH):c.893C>T (p.Ala298Val)

gnomAD frequency: 0.00001  dbSNP: rs764993096
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000550415 SCV000631943 uncertain significance Glutaric aciduria, type 1 2022-10-21 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 298 of the GCDH protein (p.Ala298Val). This variant is present in population databases (rs764993096, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with GCDH-related conditions. ClinVar contains an entry for this variant (Variation ID: 459955). 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. This variant disrupts the p.Ala298 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11058907, 15505393, 23104440, 26656312, 27672653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586768 SCV005077075 uncertain significance not specified 2024-04-22 criteria provided, single submitter clinical testing Variant summary: GCDH c.893C>T (p.Ala298Val) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250510 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.893C>T has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (examples: Goodman_1998, Schuurmans_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Glutaric Acidemia Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9711871, 37020324). ClinVar contains an entry for this variant (Variation ID: 459955). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000550415 SCV002086983 uncertain significance Glutaric aciduria, type 1 2020-08-10 no assertion criteria provided clinical testing

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