ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1262T>G (p.Ile421Ser)

dbSNP: rs199475696
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel 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 (formerly Invitae), Labcorp RCV000792932 SCV000932261 uncertain significance Phenylketonuria 2021-08-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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, Inc. RCV000792932 SCV002088617 uncertain significance Phenylketonuria 2020-09-04 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.