Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003050529 | SCV003443120 | pathogenic | Glutaric aciduria, type 1 | 2023-12-31 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 148 of the GCDH protein (p.Val148Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glutaric aciduria type I (PMID: 9600243, 24332224). ClinVar contains an entry for this variant (Variation ID: 2138244). 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%. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003050529 | SCV004039399 | pathogenic | Glutaric aciduria, type 1 | 2023-08-25 | criteria provided, single submitter | clinical testing | Variant summary: GCDH c.442G>A (p.Val148Ile) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes (gnomAD). c.442G>A has been reported in the literature in multiple bi-allelic individuals affected with Glutaric Acidemia Type 1 (examples: Schwartz_1998, Kolker_2006, Christensen_2004, and Wang_2014). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (examples: Schwartz_1998, Kolker_2006, Christensen_2004). The following publications have been ascertained in the context of this evaluation (PMID: 9600243, 16641220, 15505393, 24332224). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV003050529 | SCV004191001 | likely pathogenic | Glutaric aciduria, type 1 | 2023-10-13 | criteria provided, single submitter | clinical testing |