ClinVar Miner

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

dbSNP: rs201245932
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Total submissions: 3
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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 condition 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.

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