rs62642926

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP4PP1PM3

This summary comes from the ClinGen Evidence Repository: The c.117C>G (p.Phe39Leu) variant in PAH has been reported in multiple individuals with PKU. (PMID:23430918, 8659548, 8406445, 2063869). This variant has an extremely low allele frequency in ExAC, gnomAD, 1000 Genomes, ESP (MAF=0.00016). This variant was detected with multiple pathogenic variants: T81P, V177L (PMID:8659548), F55fsdelT (2 patients, PMID:15557004), p.I65T, p.R408W (4 patients), p.R252W, p.E280K, c.1066-11G>A, c.1315+1G>A (PMID:23430918). There is cosegregation with disease in affected siblings in 2 families PMID:2063869, 8592329). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA251537/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

9
7
3

Clinical Significance

Pathogenic reviewed by expert panel P:21O:1

Conservation

PhyloP100: 3.73
Variant links:
Genes affected
PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 6 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAHNM_000277.3 linkc.117C>G p.Phe39Leu missense_variant Exon 2 of 13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkc.117C>G p.Phe39Leu missense_variant Exon 3 of 14 NP_001341233.1
PAHXM_017019370.2 linkc.117C>G p.Phe39Leu missense_variant Exon 2 of 7 XP_016874859.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkc.117C>G p.Phe39Leu missense_variant Exon 2 of 13 1 NM_000277.3 ENSP00000448059.1 P00439

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152182
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000191
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000955
AC:
24
AN:
251412
Hom.:
0
AF XY:
0.000110
AC XY:
15
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000253
AC:
370
AN:
1461444
Hom.:
0
Cov.:
30
AF XY:
0.000250
AC XY:
182
AN XY:
727034
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000309
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
AF:
0.0000920
AC:
14
AN:
152182
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000191
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000275
Hom.:
0
Bravo
AF:
0.000147
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.000273
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:21Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Phenylketonuria Pathogenic:13
Jul 01, 1991
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Feb 16, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The PAH c.117C>G (p.Phe39Leu) variant located in the ACT domain (via InterPro) involves the alteration of a conserved nucleotide, which 3/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 11/121396 (1/11037), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals. Publications have indicated that the variant causes a mild-moderate phenotype. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The PAH c.117C>G (p.F39L) missense variant has been reported in individuals with affected with phenylketonuria (PKU), mild PKU and hyperphenylalaninemia (PMID: 8592329; 8533759; 8659548; 12655553; 15557004). -

Apr 02, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 20, 2024
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM3_very-strong, PM2, PP4, PP1 -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PAH c.117C>G (p.Phe39Leu) missense variant is well-described in the literature and has been identified individuals with varying phenotypes, ranging from classic phenylketonuria (PKU) to untreated hyperphenylalaninemia with normal intelligence (Forrest et al. 1991; Tyfield et al. 1995; Kayaalp 1997). Across a selection of the available literature the p.Phe39Leu variant has been reported in a compound heterozygous state in at least seven patients and in at least 101 of 1738 patient alleles where zygosity was not specified (Forrest et al. 1991; Guldberg et al. 1993; Tyfield et al. 1995; Zschocke et al. 1995; O'Donnell et al. 2002; Erlandsen et al. 2004; Zurflüh et al 2008; Polak et al. 2013). The p.Phe39Leu variant is more common in Scottish and Northern Irish PKU populations, with a frequency of approximately 6% and 9.5% respectively (Tyfield et al., 1995; Zschocke et al., 1995). In vitro functional analysis by Waters et al. (1999 and 2000) revealed that the variant is associated with increased protein aggregation and accelerated proteolytic degradation compared to wild type, as well as partial conversion of normal oligomeric protein forms to higher molecular weight aggregates. The p.Phe39Leu variant was absent from at least 236 controls and is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant is generally described as a BH4-responsive variant (Erlandsen et al. 2004; Zurflüh et al. 2008; Heintz et al. 2012). Based on the collective evidence, the p.Phe39Leu variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jan 13, 2022
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 10, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 20, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000277.1(PAH):c.117C>G(F39L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 8592329, 21953985, 10429004, 24368688, 26666653, and 12173030. Classification of NM_000277.1(PAH):c.117C>G(F39L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Dec 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the PAH protein (p.Phe39Leu). This variant is present in population databases (rs62642926, gnomAD 0.02%). This missense change has been observed in individual(s) with phenylketonuria, mild phenylketonuria and hyperphenylalaninemia (PMID: 2063869, 8592329, 8659548, 12655544, 12655553, 17935162). It is commonly reported in individuals of Scotland and Northern Ireland ancestry (PMID: 2063869, 8592329, 8659548, 12655544, 12655553, 17935162). ClinVar contains an entry for this variant (Variation ID: 605). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 1146119, 15557004, 17935162, 21953985, 25563416). For these reasons, this variant has been classified as Pathogenic. -

Mar 27, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 27, 2020
ClinGen PAH Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.117C>G (p.Phe39Leu) variant in PAH has been reported in multiple individuals with PKU. (PMID: 23430918, 8659548, 8406445, 2063869). This variant has an extremely low allele frequency in ExAC, gnomAD, 1000 Genomes, ESP (MAF=0.00016). This variant was detected with multiple pathogenic variants: T81P, V177L (PMID: 8659548), F55fsdelT (2 patients, PMID: 15557004), p.I65T, p.R408W (4 patients), p.R252W, p.E280K, c.1066-11G>A, c.1315+1G>A (PMID: 23430918). There is cosegregation with disease in affected siblings in 2 families PMID: 2063869, 8592329). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4, PP1. -

not provided Pathogenic:6Other:1
Aug 08, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 18, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1, PP3, PP4, PM2_moderate, PM3_very_strong -

Apr 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PAH: PM3:Very Strong, PM2, PP4:Moderate, PP1 -

Sep 13, 2017
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Nov 29, 2017
Genetic Services Laboratory, University of Chicago
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 08, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Tetrahydrobiopterin (BH4) responsiveness is inconsistent in individuals who harbor the F39L variant (Zurfluh et al., 2008; Ho et al., 2014; Jeannesson-Thivisol et al., 2015; Aldmiz-Echevarra et al., 2016); This variant is associated with the following publications: (PMID: 11461190, 21953985, 27121329, 27760515, 8659548, 12655544, 23559577, 2063869, 25087612, 16338627, 29102225, 10429004, 8592329, 23430918, 25563416, 1146119, 12655553, 30037505, 15557004, 26666653, 24368688, 29030855, 30648773, 32853555, 32668217, 32778825, 33465300, 17935162, 27535533) -

PAH-related disorder Pathogenic:1
Jul 30, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PAH c.117C>G variant is predicted to result in the amino acid substitution p.Phe39Leu. This variant is documented as causative for phenylalanine hydroxylase deficiency, when found in the homozygous or compound heterozygous state (e.g., Guldberg et al. 1996. PubMed ID: 8659548; Sarkissian et al. 2012. PubMed ID: 23430918; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). In functional studies, the p.Phe39Leu amino acid change has been reported to result in reduced PAH protein levels as well as reduced enzyme activity (Zurflüh et al. 2008. PubMed ID: 17935162; Shi et al. 2012. PubMed ID: 21953985). Data regarding the responsiveness of patients with the p.Phe39Leu amino acid substitution to tetrahydrobiopterin (BH4) is conflicting (Zurflüh et al. 2008. PubMed ID: 17935162; Sarkissian et al. 2012. PubMed ID: 23430918). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has been interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as numerous outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/605). This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1
Dec 06, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.117C>G (p.F39L) alteration is located in exon 2 (coding exon 2) of the PAH gene. This alteration results from a C to G substitution at nucleotide position 117, causing the phenylalanine (F) at amino acid position 39 to be replaced by a leucine (L). Based on data from gnomAD, the G allele has an overall frequency of 0.009% (26/282820) total alleles studied. The highest observed frequency was 0.016% (21/129140) of European (non-Finnish) alleles. This variant has been reported homozygous or with a second variant in PAH in multiple individuals diagnosed with phenylalanine hydroxylase deficiency (Forrest, 1991; Tyfield, 1995; Koch, 2005; Ho, 2014; Bayat, 2016; Ferreira, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;D;D;D
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.94
D;D;D;D
M_CAP
Pathogenic
0.44
D
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.2
M;.;.;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-5.5
D;D;D;D
REVEL
Pathogenic
0.75
Sift
Benign
0.10
T;T;D;D
Sift4G
Benign
0.18
T;T;D;.
Polyphen
1.0
D;.;.;.
Vest4
0.94
MutPred
0.87
Loss of catalytic residue at F39 (P = 0.0777);.;Loss of catalytic residue at F39 (P = 0.0777);Loss of catalytic residue at F39 (P = 0.0777);
MVP
0.98
MPC
0.25
ClinPred
0.87
D
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.91
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs62642926; hg19: chr12-103306620; API