Submissions for variant NM_000159.4(GCDH):c.901G>A (p.Val301Met)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003050530	SCV003443130	pathogenic	Glutaric aciduria, type 1	2023-09-17	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 2138250). This missense change has been observed in individual(s) with glutaric acidemia, type 1 (PMID: 24332224, 32508882). 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 (rs751186776, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 301 of the GCDH protein (p.Val301Met). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003050530	SCV004199255	likely pathogenic	Glutaric aciduria, type 1	2023-11-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479465	SCV004223347	uncertain significance	not specified	2024-09-09	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.901G>A (p.Val301Met) results in a 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 250462 control chromosomes. c.901G>A has been reported in the literature as a compound heterozygous genotype in at least two individuals affected with Glutaric Acidemia Type 1 (e.g. Wang_2014, Xiao_2020). These data indicate that the variant may be associated with disease. 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: 34306040, 37020324, 24332224, 32508882). ClinVar contains an entry for this variant (Variation ID: 2138250). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.