Submissions for variant NM_000159.4(GCDH):c.743C>T (p.Pro248Leu)

gnomAD frequency: 0.00003  dbSNP: rs1057516344

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411040	SCV000485501	likely pathogenic	Glutaric aciduria, type 1	2015-12-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000411040	SCV001443026	pathogenic	Glutaric aciduria, type 1	2020-03-01	criteria provided, single submitter	clinical testing	Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PM2,PM3_Strong,PP3
GeneDx	RCV001556801	SCV001778443	pathogenic	not provided	2020-11-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with significantly reduced protein expression and an increase in protein degradation compared to wild type (Schmiesing et al., 2017); This variant is associated with the following publications: (PMID: 32777384, 32240488, 32992790, 16377226, 10699052, 15505393, 11058907, 15505400, 16641220, 11073722, 19433437, 28062662, 17622945, 29458885, 28438223, 20978942, 15505399, 27527619)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411040	SCV003928817	pathogenic	Glutaric aciduria, type 1	2023-04-17	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.743C>T (p.Pro248Leu) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251420 control chromosomes. c.743C>T has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with Glutaric Acidemia Type 1 (example, Christensen_2004, Klavuz_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 1-5% of normal glutaryl-CoA dehydrogenase activity in fibroblasts from a homozygous individual (Christensen_2004). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000411040	SCV004199241	pathogenic	Glutaric aciduria, type 1	2023-06-22	criteria provided, single submitter	clinical testing
Invitae	RCV000411040	SCV004297911	pathogenic	Glutaric aciduria, type 1	2023-04-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 370244). This missense change has been observed in individual(s) with glutaryl CoA dehydrogenase deficiency (PMID: 16377226, 28438223, 32240488). 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 (no rsID available, gnomAD 0.03%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 248 of the GCDH protein (p.Pro248Leu).