Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001344773 | SCV001538850 | uncertain significance | Glutaric aciduria, type 1 | 2022-06-20 | 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 243 of the GCDH protein (p.Arg243Trp). This variant is present in population databases (rs549254182, gnomAD 0.02%). This missense change has been observed in individual(s) with a positive newborn screening result for GCDH-related disease (PMID: 32778825). ClinVar contains an entry for this variant (Variation ID: 1041029). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Department of Pathology and Laboratory Medicine, |
RCV001354225 | SCV001548785 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The GCDH p.Arg243Trp variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs549254182), Cosmic (FATHMM prediction of pathogenic; score 0.80). The variant was identified in control databases in 6 of 246230 chromosomes at a frequency of 0.000024 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: East Asian in 3 of 17246 chromosomes (freq: 0.000174) and European (Non-Finnish) in 3 of 111692 chromosomes (freq: 0.000027), while the variant was not observed in the African, Ashkenazi Jewish, European (Finnish), Latino, Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, GeneSplicer) do not predict a difference in splicing. The p.Arg243 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. | |
| Natera, |
RCV001344773 | SCV002086973 | uncertain significance | Glutaric aciduria, type 1 | 2020-02-26 | no assertion criteria provided | clinical testing |