ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1250A>G (p.Tyr417Cys)

dbSNP: rs1371700813
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001789813 SCV002032197 likely pathogenic Phenylketonuria 2020-08-13 reviewed by expert panel curation The c.1250A>G (p.Tyr417Cys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 21147011). This variant has extremely low frequency in gnomAD (MAF=0.00001). It was detected with the pathogenic variant IVS10-11G>A (PMID: 28593914). Computational evidence support a deleterious effect. Another missense change at the same amino acid (p.Tyr417His) is interpreted as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PM3_supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp RCV001789813 SCV004294253 pathogenic Phenylketonuria 2023-03-28 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 417 of the PAH protein (p.Tyr417Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 21147011, 29499199, 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 1327551). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 2230084). This variant disrupts the p.Tyr417 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12501224, 18538294, 23500595). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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