rs62642913
Variant summary
Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PM3PM2_SupportingPP4_Moderate
This summary comes from the ClinGen Evidence Repository: 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: PathogenicSupporting Criteria: PS3_supporting; PM2_supporting; PM3_VeryStrong; PP4_Moderate; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229855/MONDO:0009861/006
Frequency
Consequence
NM_000277.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PAH | NM_000277.3 | c.929C>T | p.Ser310Phe | missense_variant | 9/13 | ENST00000553106.6 | NP_000268.1 | |
| PAH | NM_001354304.2 | c.929C>T | p.Ser310Phe | missense_variant | 10/14 | NP_001341233.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Phenylketonuria Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 16, 2018 | 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. - |
| Pathogenic, reviewed by expert panel | curation | ClinGen PAH Variant Curation Expert Panel | Dec 30, 2023 | 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 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 01, 2020 | Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PM2,PM5,PM3_Strong,PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 28, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Other:1
| not provided, no classification provided | literature only | DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at