Submissions for variant NM_000277.3(PAH):c.1012G>T (p.Asp338Tyr)

gnomAD frequency: 0.00001  dbSNP: rs62516150

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000794431	SCV002540171	pathogenic	Phenylketonuria	2020-11-09	reviewed by expert panel	curation	The c.1012G>T (p.Asp338Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 27121329, PMID: 21147011). This variant has an extremely low allele frequency in gnomAD (MAF=0.00002). This variant was detected with multiple pathogenic variants: p.P281L (PMID: 16601866); p.F299C (PMID: 7913581); p.I65T (PMID: 17502162); c.1066-11G>A (PMID: 31623983); p.Arg261*, p.Phe55Leu (PMID: 26655635). Multiple lines of computational evidence do not agree on predicted pathogenicity (Deleterious in SIFT, PolyPhen, Polymorphism in MutationTaster). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate.
Invitae	RCV000794431	SCV000933838	pathogenic	Phenylketonuria	2023-07-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 102468). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 7913581, 17502162, 19292873, 25882749). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs62516150, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 338 of the PAH protein (p.Asp338Tyr).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000794431	SCV001362287	pathogenic	Phenylketonuria	2019-09-09	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1012G>T (p.Asp338Tyr) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251188 control chromosomes. c.1012G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria- eg Rozen_1994, Kayaalp_1997, Carter_1998, Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000794431	SCV002060032	pathogenic	Phenylketonuria	2021-11-17	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.1012G>T(D338Y) is a missense variant classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the D338Y variant can be associated with any form of this disease. D338Y has been observed in cases with relevant disease (PMID: 32668217, 7913581, 26655635). Functional assessments of this variant are not available in the literature. D338Y has been observed in population frequency databases (gnomAD: NFE 0.002%). In summary, NM_000277.1(PAH):c.1012G>T(D338Y) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Baylor Genetics	RCV000794431	SCV004209635	pathogenic	Phenylketonuria	2023-07-19	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088699	SCV000119279	not provided	not provided		no assertion provided	not provided