Submissions for variant NM_000277.3(PAH):c.250G>T (p.Asp84Tyr)

gnomAD frequency: 0.00003  dbSNP: rs62514902

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000761308	SCV004222641	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The c.250G>T (p.Asp84Tyr) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 9634518). This variant has an extremely low allele frequency (MAF=0.00002) in gnomAD. This variant was detected with multiple pathgenic variants: F39L (PMID:11328945), Y356X (PMID: 15503242), P281L (PMID: 23430918), R158Q (PMID: 19609714) (PM3_VS). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.819) (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2_supporting, PP4_Moderate, PP3.
Eurofins Ntd Llc (ga)	RCV000088883	SCV000228839	pathogenic	not provided	2014-07-16	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761308	SCV000891286	likely pathogenic	Phenylketonuria	2017-10-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000761308	SCV002572261	pathogenic	Phenylketonuria	2024-05-06	criteria provided, single submitter	clinical testing	Variant summary: PAH c.250G>T (p.Asp84Tyr) results in a non-conservative amino acid change located in the ACT domain (IPR002912) 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 8e-06 in 251442 control chromosomes (gnomAD). c.250G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (examples: Koch_1997, Levy_2001, Lee_2004, Langenbeck_2009, Sarkissian_2012, Shirzadeh_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 9169088, 19609714, 15503242, 11328945, 23430918, 30159852). ClinVar contains an entry for this variant (Variation ID: 102639). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000761308	SCV003441011	pathogenic	Phenylketonuria	2023-09-06	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: 102639). This missense change has been observed in individual(s) with phenylketonuria (PMID: 32668217). This variant is present in population databases (rs62514902, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 84 of the PAH protein (p.Asp84Tyr).
Baylor Genetics	RCV000761308	SCV005053818	pathogenic	Phenylketonuria	2024-03-06	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798776	SCV005420355	pathogenic	Hyperphenylalaninemia	2024-10-04	criteria provided, single submitter	research	PM2,PP3,PM3,PP4
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088883	SCV000119480	not provided	not provided		no assertion provided	not provided