Submissions for variant NM_000277.3(PAH):c.307G>T (p.Gly103Cys)

gnomAD frequency: 0.00001  dbSNP: rs752792040

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000669128	SCV004015307	uncertain significance	Phenylketonuria	2023-07-23	reviewed by expert panel	curation	The c.307G>T (p.Gly103Cys) variant in PAH has been reported in 2 patients with PKU (BH4 deficiency not assessed/reported) (PP4; PMID: 17502162, 24368688). It was detected in unknown phase with a pathogenic variant c.1066-11G>A (PMID: 17502162) and a likely pathogenic variant p.Y154F (PMID: 24368688). This variant has extremely low frequency in ExAC (MAF=0.00001). Computational evidence supports a deleterious effect (REVEL=0.819). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2_supporting, PM3_supporting, PP3_moderate.
Counsyl	RCV000669128	SCV000793842	uncertain significance	Phenylketonuria	2017-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV000669128	SCV002233831	pathogenic	Phenylketonuria	2023-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 103 of the PAH protein (p.Gly103Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hyperphenylalaninemia (PMID: 17502162, 24368688, 32668217; Invitae). ClinVar contains an entry for this variant (Variation ID: 553638). 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 with a negative predictive value of 80%. This variant disrupts the p.Gly103 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31355225). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000669128	SCV002512202	uncertain significance	Phenylketonuria	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689843	SCV005185122	uncertain significance	not specified	2024-05-21	criteria provided, single submitter	clinical testing	Variant summary: PAH c.307G>T (p.Gly103Cys) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.307G>T has been reported in the literature in compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Dobrowolski_2007, Ho_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17502162, 32668217, 24368688). ClinVar contains an entry for this variant (Variation ID: 553638). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.