rs5030856

Positions:

chr12-102843676-T-C

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3PP3PP4_ModeratePM2

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

Clinical Significance

Pathogenic reviewed by expert panel P:20O: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]

PAH links:

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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.1169A>G	p.Glu390Gly	missense_variant	11/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.1169A>G	p.Glu390Gly	missense_variant	12/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1169A>G	p.Glu390Gly	missense_variant	11/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151974

Hom.:

Cov.:

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:

AN:

251312

Hom.:

AF XY:

0.000118

AC XY:

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.:

Cov.:

AF XY:

0.000118

AC XY:

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:

AN:

151974

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

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.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:12

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Oct 01, 2018	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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). 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 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1999	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	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; ZurflÃ¼h 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 (ZurflÃ¼h 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 20, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 16, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3_VS,PP3,PP4_M. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 26, 2023	Criteria applied: PM3_VSTR,PP4_MOD,PM2_SUP,PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 22, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Apr 25, 2024	ACMG Criteria: PM2, PP3, PS3, PM3, PP5; Variant was found in heterozygous state -

not provided

Pathogenic:4Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 27, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 21, 2020	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)). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -

Hyperphenylalaninemia

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 03, 2017	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. -

PAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 07, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Apr 11, 2023

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

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.1

M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.52

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over