ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.668A>T (p.Asn223Ile)

dbSNP: rs201245932
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 RCV000664486 SCV002032223 likely pathogenic Phenylketonuria 2020-06-01 reviewed by expert panel curation The c.668A>T (p.Asn223Ile) variant in PAH has been reported in 2 individuals with PKU and MHP (BH4 deficiency excluded). (PMID: 30050108). This variant has extremely low frequency in gnomAD (MAF=0.0001307). This variant was detected with in trans with p.Y166* (PMID: 30050108). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.
Counsyl RCV000664486 SCV000788452 uncertain significance Phenylketonuria 2018-02-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003420168 SCV004106534 likely pathogenic PAH-related disorder 2022-09-30 criteria provided, single submitter clinical testing The PAH c.668A>T variant is predicted to result in the amino acid substitution p.Asn223Ile. This variant has been reported in at least two individuals with phenylketonuria, one of which was compound heterozygous with a null allele (Li et al. 2015. PubMed ID: 26503515; Li at al. 2018. PubMed ID: 30050108). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-103248952-T-A). It is classified as Likely Pathogenic in ClinVar by a ClinGen expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/549912/). Taken together, we interpret this variant to be likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004800513 SCV005422118 uncertain significance not specified 2024-10-25 criteria provided, single submitter clinical testing Variant summary: PAH c.668A>T (p.Asn223Ile) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251334 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.668A>T has been reported in the literature in an individual affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) without a reported second allele (Li_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26503515). ClinVar contains an entry for this variant (Variation ID: 549912). Based on the evidence outlined above, the variant was classified as uncertain significance.

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.