rs5030856

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PP4_ModeratePM2PM3

This summary comes from the ClinGen Evidence Repository: The c.1169A>G (p.Glu390Gly) variant in PAH has been reported on at least 47 alleles, most often with Mild Hyperphenylalaninemia. (BH4 deficiency excluded). (PP4_Moderate; PMID:8088845; PMID:21147011). This variant has an extremely low allele frequency (MAF=0.00018 in gnomAD) (PM2; http://gnomAD.broadinstitute.org). This variant was detected in trans with IVS-12nt1, L333F (Pathogenic in ClinVar) + 8 homozygotes (PM3_Very-strong; PMID:10479481; PMID:21147011; PMID:8088845). Computational prediction tools and conservation analysis suggest that the c.1169A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA114367/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

12
5
2

Clinical Significance

Pathogenic reviewed by expert panel P:21O:1

Conservation

PhyloP100: 8.02
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 7 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.
PP3
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.1169A>G p.Glu390Gly missense_variant Exon 11 of 13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkc.1169A>G p.Glu390Gly missense_variant Exon 12 of 14 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkc.1169A>G p.Glu390Gly missense_variant Exon 11 of 13 1 NM_000277.3 ENSP00000448059.1 P00439

Frequencies

GnomAD3 genomes
AF:
0.0000790
AC:
12
AN:
151974
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000995
AC:
25
AN:
251312
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135804
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
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:
0.000163
GnomAD4 exome
AF:
0.000101
AC:
147
AN:
1461624
Hom.:
0
Cov.:
31
AF XY:
0.000118
AC XY:
86
AN XY:
727116
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
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:
0.000121
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000790
AC:
12
AN:
151974
Hom.:
0
Cov.:
31
AF XY:
0.0000808
AC XY:
6
AN XY:
74236
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000221
Hom.:
0
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.00
EpiControl
AF:
0.000296

ClinVar

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

Submissions by phenotype

Phenylketonuria Pathogenic:12
Jul 26, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Criteria applied: PM3_VSTR,PP4_MOD,PM2_SUP,PP3 -

Aug 16, 2019
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3_VS,PP3,PP4_M. -

Jan 14, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 390 of the PAH protein (p.Glu390Gly). This variant is present in population databases (rs5030856, gnomAD 0.02%). This missense change has been observed in individual(s) with mild hyperphenylalaninemia and mild phenylketonuria (PMID: 8088845, 10472529, 10479481, 12655552, 17935162, 21147011, 21871829, 25596310, 26803807). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 625). 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: 17935162, 22300847, 26803807). For these reasons, this variant has been classified as Pathogenic. -

Aug 14, 2018
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Across a selection of the available literature, the PAH c.1169A>G (p.Glu390Gly) missense variant has been identified in a compound heterozygous state in three individuals with phenylalanine hydroxylase deficiency and in one child with non-PKU hyperphenylalaninemia identified by newborn screening and in three individuals with mild hyperhpenylalaninemila. The variant was also identified in 23/630 alleles of individuals with BH4-responsive mild hyperhpenylalaninemila (Guldberg et al. 1994; Zurflüh et al. 2008; Couce et al. 2013; Trunzo et al. 2013). The p.Glu390Gly variant was absent from 110 controls and is reported at a frequency of 0.00018 in the European (non-Finnish) population of the Genome Aggregation Database. Averaged across different cell systems, the p.Glu390Gly variant showed 72.7% residual enzyme activity (Zurflüh et al. 2008), while expression in COS-7 cells revealed that the p.[Glu390Gly];[Arg408Trp] genotype, a recurrent genotype in European and Middle Eastern populations, showed 8.3% residual activity compared to wild type (Danecka et al. 2015). Based on the collective evidence, the p.Glu390Gly 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. -

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

- -

Nov 20, 2020
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 30, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 1999
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Oct 01, 2018
ClinGen PAH Variant Curation Expert Panel
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.1169A>G (p.Glu390Gly) variant in PAH has been reported on at least 47 alleles, most often with Mild Hyperphenylalaninemia. (BH4 deficiency excluded). (PP4_Moderate; PMID: 8088845; PMID: 21147011). This variant has an extremely low allele frequency (MAF=0.00018 in gnomAD) (PM2; http://gnomAD.broadinstitute.org). This variant was detected in trans with IVS-12nt1, L333F (Pathogenic in ClinVar) + 8 homozygotes (PM3_Very-strong; PMID: 10479481; PMID: 21147011; PMID: 8088845). Computational prediction tools and conservation analysis suggest that the c.1169A>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong -

Apr 20, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 22, 2016
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 25, 2024
Institute of Immunology and Genetics Kaiserslautern
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG Criteria: PM2, PP3, PS3, PM3, PP5; Variant was found in heterozygous state -

not provided Pathogenic:5Other:1
-
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Mar 19, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PM2, PM3_very_strong -

Oct 10, 2023
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; Classified as being a tetrahydrobiopterin (BH4) responsive variant (PMID: 17935162, 23559577); This variant is associated with the following publications: (PMID: 10472529, 25750018, 23500595, 34828281, 31355225, 26666653, 30963030, 21147011, 22763404, 25087612, 8088845, 11914042, 25596310, 8098245, 28676969, 24048906, 22300847, 15557004, 26803807, 10479481, 31589614, 34426522, 33375644, 32778825, 33465300, 29288420, 23792259, 23559577, 35355500, 36537053, 35328070, 35339094, 35405047, 17935162) -

Oct 21, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant has been reported in multiple homozygous and compound heterozygous individuals affected with mild hyperphenylalaninemia or mild PKU and has been characterized as BH4-responsive in the published literature (PMID: 10472529 (1999), 19394257 (2009), 21147011 (2011), 22300847 (2012), 26803807 (2016), 31623983 (2019)). Functional studies have shown this variant reduces PAH activity to 42-62% (PMID: 21147011 (2011), 22300847 (2012), 26803807 (2016)). -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PAH: PM3:Very Strong, PM2, PS3:Moderate, PP4 -

Sep 27, 2013
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hyperphenylalaninemia Pathogenic:2
Jan 03, 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.1169A>G (p.Glu390Gly) variant involves the alteration of a conserved nucleotide, present in catalytic domain of the protein (Couce_2013) and is predicted to be damaging by 5/5 in silico tools. This variant was found in 12/121202 control chromosomes at a frequency of 0.000099, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant is widely described as one of the frequent pathogenic variants that causes hyperphenylalaninemia with consistent genotype-phenotype data and functional studies. Eight homozygotes with this variant were responsive to BH4 (Dobrowolski_2011) which can be attributed to mild functional effect of this variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -

Aug 01, 1999
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

PAH-related disorder Pathogenic:1
Dec 07, 2023
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PAH c.1169A>G variant is predicted to result in the amino acid substitution p.Glu390Gly. This variant has been mainly reported to be causative for mild hyperphenylalaninemia (HPA; Guldberg et al. 1994. PubMed ID: 8088845; Bénit et al. 1999. PubMed ID: 10479481; Dobrowolski et al. 2011. PubMed ID: 21147011; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). The p.Glu390Gly substitution has been reported to result in a PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). This variant has been classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel, as well as multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/625/). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Mild hyperphenylalaninemia Pathogenic:1
Apr 11, 2023
Molecular Genetics, Royal Melbourne Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change in PAH is predicted to replace glutamic acid with glycine at codon 390, p.(Glu390Gly). The glutamic acid residue is highly conserved (100 vertebrates, UCSC), and is located in BH4 AAA hydroxyl domain. There is a moderate physicochemical difference between glutamic acid and glycine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.016% (21/129,082 alleles) in the European (non-Finnish) population, which is consistent with phenylalanine hydroxylase deficiency. This variant has been detected in multiple individuals with mild hyperphenylalaninaemia (MHP) in the homozygous state and compound heterozygous with a second pathogenic allele. It is one of the most common variants associated with the MHP phenotype (PMID: 31623983, 32668217). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.973). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP3_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;D
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.1
M;.
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-5.0
D;D
REVEL
Pathogenic
0.97
Sift
Uncertain
0.011
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
0.99
D;.
Vest4
0.93
MVP
0.99
MPC
0.055
ClinPred
0.76
D
GERP RS
5.3
Varity_R
0.77
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
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: rs5030856; hg19: chr12-103237454; API