Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001248714 | SCV001448664 | likely pathogenic | Phenylketonuria | 2020-07-25 | reviewed by expert panel | curation | The NM_000277.3:c.545A>G (p.Glu182Gly) variant is a missense variant in exon 6/13 of PAH. The variant was reported in confirmed trans with the p.R261Q allele (Pathogenic per ClinGen PAH VCEP) among two siblings with mild hyperphenylalanemia; BH4 deficiency was not noted to have been formally excluded (PMID: 26542770) (PP1; PM3). The variant has also been previously reported among “two alleles†in a cohort of Armenian PKU patients among whom BH4 deficiency was excluded; no further detail appears to be given (PMID: 10541324) (PP4_Moderate). It has also been noted in ClinVar (ID 102731), without a classification. Three heterozygotes and zero homozygotes for the variant are present in gnomAD, corresponding to a global AF of 0.0000119 and maximum population frequency of 0.0000264 (non-Finnish European population), under the frequency cutoff of 0.0002 for use of PM2 (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.929) (PP3). Classification: Likely Pathogenic Supporting Criteria: PM2; PM3; PP1; PP4_Moderate; PP3 |
Invitae | RCV001248714 | SCV001422220 | pathogenic | Phenylketonuria | 2021-12-31 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu182 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31355225). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102731). This missense change has been observed in individual(s) with phenylketonuria (PMID: 26542770). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs199475617, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 182 of the PAH protein (p.Glu182Gly). |
Baylor Genetics | RCV001248714 | SCV004201958 | likely pathogenic | Phenylketonuria | 2022-11-16 | criteria provided, single submitter | clinical testing | |
De |
RCV000088980 | SCV000119584 | not provided | not provided | no assertion provided | not provided |