Submissions for variant NM_000159.4(GCDH):c.397G>T (p.Val133Leu)

dbSNP: rs746388510

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671234	SCV000796189	uncertain significance	Glutaric aciduria, type 1	2017-12-04	criteria provided, single submitter	clinical testing
GeneDx	RCV001766447	SCV001989570	uncertain significance	not provided	2020-09-17	criteria provided, single submitter	clinical testing	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: 27397597)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671234	SCV003443126	pathogenic	Glutaric aciduria, type 1	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 133 of the GCDH protein (p.Val133Leu). This variant is present in population databases (rs746388510, gnomAD 0.03%). This missense change has been observed in individual(s) with glutaric aciduria type 1 (PMID: 27397597). ClinVar contains an entry for this variant (Variation ID: 555414). 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 with a positive predictive value of 80%. This variant disrupts the p.Val133 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10699052; Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230569	SCV003928819	uncertain significance	not specified	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.397G>T (p.Val133Leu) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251458 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.397G>T has been reported in the literature in individuals affected with Glutaric Acidemia Type 1 (Schillaci_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27397597). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and pathogenic(n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.