Submissions for variant NM_000277.3(PAH):c.929C>T (p.Ser310Phe)

dbSNP: rs62642913

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000552302	SCV004222645	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The NM_000277.1(PAH):c.929C>T (p.Ser310Phe) variant is a missense variant in exon 9/13 of PAH. The variant has been found to result in <1% of wild-type PAH enzyme activity in a standard cDNA and an Intinc system (PMID: 18590700) (PS3_supporting). It has been found in at least 8 PKU patients, including among those whom BH4 deficiency was excluding and in trans with other Pathogenic or Likely Pathogenic alleles (PM3_VeryStrong (4.75 points); PP4_Moderate). It has been found in 2 alleles in a survey of German PKU patients (PMID: 12655553); in trans with the c.442-1G>A (Pathogenic in ClinVar and by ClinGen PAH VCEP) variant in a Korean patient with moderate PKU (plasma Phe 600-1200 umol/L) with BH4 deficiency excluded by urinary pterin analysis and dihydropteridine reductase (DHPR) assay (PMID: 15503242). It has been found in as a homozygous variant in a Syrian patient with classic PKU (plasma Phe 1262 umol/L) (PMID: 23856132). It has been found in two Chinese patients with classic PKU and BH4 deficiency excluded via analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes: one harbored it in trans with the p.R111* variant (Pathogenic in ClinVar and by ClinGen PAH VCEP) and one in trans with the p.Y356* variant (Pathogenic in ClinVar and by ClinGen PAH VCEP) (PMID: 30050108). It has been found in a Chinese patient with mild hyperphenylalanemia (plasma Phe 120-360 umol/L) in trans with p.R241C (Pathogenic in ClinVar and by ClinGen PAH VCEP); BH4 deficiency was excluded (PMID: 25894915). It has been found in trans with p.F302V (unclassified) in a Chinese patient with mild PKU (plasma Phe 360–1200 μmol/L) and BH4 deficiency excluded (PMID: 30459323). It has been reported in trans with c.1066-3C>T (Pathogenic/Likely Pathogenic in ClinVar and by ClinGen PAH VCEP)in a PKU patient (PMID: 23430918). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.993) (PP3). Classification: Pathogenic Supporting Criteria: PS3_supporting; PM2_supporting; PM3_VeryStrong; PP4_Moderate; PP3
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552302	SCV000629227	pathogenic	Phenylketonuria	2018-07-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in individuals affected with phenylketonuria or mild hyperphenylalaninemia either as homozygous or in combination with other PAH variants in many of the other cases (PMID: 15503242, 23856132, 12655553, 19915519, 26503515, 23932990). ClinVar contains an entry for this variant (Variation ID: 102899). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with phenylalanine at codon 310 of the PAH protein (p.Ser310Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000552302	SCV001443018	likely pathogenic	Phenylketonuria	2020-03-01	criteria provided, single submitter	clinical testing	Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PM2,PM5,PM3_Strong,PP3
Baylor Genetics	RCV000552302	SCV004201325	pathogenic	Phenylketonuria	2023-10-28	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089162	SCV000119777	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000552302	SCV001463129	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing