Submissions for variant NM_000159.4(GCDH):c.1147C>T (p.Arg383Cys)

gnomAD frequency: 0.00007  dbSNP: rs150938052

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169204	SCV000220457	likely pathogenic	Glutaric aciduria, type 1	2014-06-29	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169204	SCV001585091	pathogenic	Glutaric aciduria, type 1	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 383 of the GCDH protein (p.Arg383Cys). This variant is present in population databases (rs150938052, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 15505393, 28438223, 30298489). ClinVar contains an entry for this variant (Variation ID: 188852). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GCDH protein function with a positive predictive value of 80%. This variant disrupts the p.Arg383 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been observed in individuals with GCDH-related conditions (PMID: 15505393, 30203563), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169204	SCV004199230	pathogenic	Glutaric aciduria, type 1	2024-03-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004017449	SCV004849022	likely pathogenic	Inborn genetic diseases	2015-03-25	criteria provided, single submitter	clinical testing	The c.1147C>T (p.R383C) alteration is located in exon 11 (coding exon 10) of the GCDH gene. This alteration results from a C to T substitution at nucleotide position 1147, causing the arginine (R) at amino acid position 383 to be replaced by a cysteine (C). The heterozygous missense change is ultra rare in healthy individuals:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the GCDH c.1147C>T alteration was observed in 1 among 13006 total alleles studied (0.01%). Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project. This variant is reported in the SNPDatabase as rs150938052. The p.R383 amino acid is conserved throughout available vertebrates. The amino acid is located in a functionally important protein domain:_x000D_ The p.R383C amino acid is located in the acyl-coenzyme A oxidase domain (PLN02526 ). Based on the available evidence, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169204	SCV005395036	pathogenic	Glutaric aciduria, type 1	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: GCDH c.1147C>T (p.Arg383Cys) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251458 control chromosomes. c.1147C>T has been reported in the literature in multiple individuals affected with Glutaric Acidemia Type 1 (example: Bijarnia_2008, Boy_2017, Chen_2018, Klavuz_2021). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1148G>A,p.Arg383His), supporting the critical relevance of codon 383 to GCDH protein function. The following publications have been ascertained in the context of this evaluation (PMID: 28438223, 30298489, 33578440, 18683078). ClinVar contains an entry for this variant (Variation ID: 188852). Based on the evidence outlined above, the variant was classified as pathogenic.
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000169204	SCV005417387	pathogenic	Glutaric aciduria, type 1		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Moderate+PM3_VeryStrong+PP4
Department of Biotechnology and Microbiology, Karnatak University Dharwad	RCV000169204	SCV000891777	uncertain significance	Glutaric aciduria, type 1	2019-01-03	no assertion criteria provided	research
Natera, Inc.	RCV000169204	SCV002086992	pathogenic	Glutaric aciduria, type 1	2021-08-12	no assertion criteria provided	clinical testing