Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000421572 | SCV000516678 | pathogenic | not provided | 2015-04-06 | criteria provided, single submitter | clinical testing | The R313W missense variant has been reported previously in association withGA1 (Goodman et al.,1998 ). This variant is associated with 0.2% of normal glutaryl-CoAdehydrogenase activity when expressed in E. coli (Goodman et al., 1998). Therefore, we consider this variant to be pathogenic. |
Counsyl | RCV000671835 | SCV000796859 | likely pathogenic | Glutaric aciduria, type 1 | 2018-01-03 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000671835 | SCV001221791 | pathogenic | Glutaric aciduria, type 1 | 2024-01-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 313 of the GCDH protein (p.Arg313Trp). This variant is present in population databases (rs779315456, gnomAD 0.006%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 15505393, 25762492, 26071121). ClinVar contains an entry for this variant (Variation ID: 379529). 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%. Experimental studies have shown that this missense change affects GCDH function (PMID: 9711871). For these reasons, this variant has been classified as Pathogenic. |
Fulgent Genetics, |
RCV000671835 | SCV002811474 | likely pathogenic | Glutaric aciduria, type 1 | 2021-08-03 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002524845 | SCV003755442 | pathogenic | Inborn genetic diseases | 2022-02-04 | criteria provided, single submitter | clinical testing | The c.937C>T (p.R313W) alteration is located in exon 9 (coding exon 8) of the GCDH gene. This alteration results from a C to T substitution at nucleotide position 937, causing the arginine (R) at amino acid position 313 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (2/249998) total alleles studied. The highest observed frequency was 0.01% (2/30616) of South Asian alleles. This variant has been reported in the homozygous and compound heterozygous states in patients with clinical and biochemical features of glutaricaciduria (Christensen, 2004; Wang, 2014; Gupta, 2015; Radha Rama Devi, 2016; Pokora, 2019). In addition, another variant at this position (p.R313Q) has also been reported in affected patients (Christensen, 2004; Wang, 2014). This amino acid position is highly conserved in available vertebrate species. In vitro studies demonstrated that this variant resulted in 0.2% residual enzyme activity when expressed in E. coli (Goodman, 1998). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. |
Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV000671835 | SCV004101559 | uncertain significance | Glutaric aciduria, type 1 | criteria provided, single submitter | clinical testing | The GCDH c.937C>T variant has been observed to be homozygous or in combination with another GCDH variant in several individuals affected with glutaric acidemia (Gupta et. al., 2015; Christensen et. al., 2004) This variant has been reported to affect GCDH protein function (Goodman et. al., 1998). The p.Arg313Trp variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.0008% in gnomAD database. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid change p.Arg313Trp in GCDH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 313 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. The above variant has been observed in spouse (RAJA_20400112292). | |
Baylor Genetics | RCV000671835 | SCV004199246 | pathogenic | Glutaric aciduria, type 1 | 2023-04-30 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000671835 | SCV004238214 | likely pathogenic | Glutaric aciduria, type 1 | 2023-08-10 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV000671835 | SCV001456392 | pathogenic | Glutaric aciduria, type 1 | 2020-09-16 | no assertion criteria provided | clinical testing |