Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000792932 | SCV001762303 | likely pathogenic | Phenylketonuria | 2020-07-03 | reviewed by expert panel | curation | The NM_000277.3:c.1262T>G (p.Ile421Ser) variant is a missense variant in exon 12/13 of PAH. The variant has been previously reported in an Austrian patient with PKU (plasma Phe 780 umol/L) in confirmed trans with the p.F39L variant (ClinVar Pathogenic (ID 605) and Pathogenic by ClinGen PAH VCEP); BH4 deficiency was excluded by urinary pterins and dihydropterine reductase assays (PMID: 22526846) (PM3; PP4_Moderate). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.969) (PP3). Classification: Likely Pathogenic Supporting Criteria: PM2; PM3; PP4_Moderate; PP3 |
Labcorp Genetics |
RCV000792932 | SCV000932261 | uncertain significance | Phenylketonuria | 2021-08-28 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV004702423 | SCV005205472 | uncertain significance | not specified | 2024-06-25 | criteria provided, single submitter | clinical testing | Variant summary: PAH c.1262T>G (p.Ile421Ser) results in a non-conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal (IPR0197740) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1262T>G has been reported in the literature in at least an individual affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; example: Sterl_2013). This data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant (c.1262T>C; p.Ile421Thr) affecting the same codon has been classified as pathogenic in ClinVar (Variation ID: 102582), supporting the critical relevance of codon 421 to PAH protein function. The following publication haS been ascertained in the context of this evaluation (PMID: 22526846). ClinVar contains an entry for this variant (Variation ID: 639999). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
Natera, |
RCV000792932 | SCV002088617 | uncertain significance | Phenylketonuria | 2020-09-04 | no assertion criteria provided | clinical testing |