Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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 | |
Prevention |
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, |
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. |