Submissions for variant NM_000277.3(PAH):c.811C>T (p.His271Tyr)

gnomAD frequency: 0.00001  dbSNP: rs62517164

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000758116	SCV000886593	uncertain significance	Phenylketonuria	2018-12-10	reviewed by expert panel	curation	The c.811C>T (p.His271Tyr) variant in PAH has been reported in 2 unrelated PKU patients. BH4 deficiencies not assessed. (PMID: 9012412) A deleterious effect is predicted in SIFT, Polyphen2, MutationTaster, and REVEL=0.978. This variant has an extremely low frequency in ExAC, 1000G, ESP, and gnomAD (MAF=0.00001). . In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4.
GeneDx	RCV000089108	SCV001758213	uncertain significance	not provided	2020-01-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in two unrelated individuals with PKU, however a second variant not described in either patient (Tyfield et al., 1997); This variant is associated with the following publications: (PMID: 9012412, 25087612)
Institute of Human Genetics, University Hospital Muenster	RCV004584351	SCV002578038	uncertain significance	See cases	2021-12-08	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP3,BP1
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758116	SCV003441283	likely pathogenic	Phenylketonuria	2023-09-15	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.His271 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18299955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is not present in population databases (gnomAD no frequency). 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 expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102849). This missense change has been observed in individual(s) with phenylketonuria (PMID: 9012412). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 271 of the PAH protein (p.His271Tyr).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089108	SCV000119715	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000758116	SCV002088643	uncertain significance	Phenylketonuria	2020-10-16	no assertion criteria provided	clinical testing