rs199475598

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong

The NM_000277.3(PAH):c.165T>G(p.Phe55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000959 in 1,605,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F55S) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 3.37

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 15 ACMG points.

PM1

In a helix (size 10) in uniprot entity PH4H_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000277.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-102912795-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

PP5

Variant 12-102912794-A-C is Pathogenic according to our data. Variant chr12-102912794-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102912794-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PAH	NM_000277.3 linkuse as main transcript	c.165T>G	p.Phe55Leu	missense_variant	2/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.165T>G	p.Phe55Leu	missense_variant	3/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.165T>G	p.Phe55Leu	missense_variant	2/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.165T>G	p.Phe55Leu	missense_variant	2/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251386

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000925

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:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000854

AC:

124

AN:

1452834

Hom.:

Cov.:

AF XY:

0.0000816

AC XY:

AN XY:

723410

show subpopulations

Gnomad4 AFR exome

AF:

0.0000901

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000698

Gnomad4 OTH exome

AF:

0.0000998

GnomAD4 genome

AF:

0.000197

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.000227

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000277.1(PAH):c.165T>G(F55L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 30367646, 27121329, 26655635, 9298832, 18538294, 18299955, 11678552, 23932990, 23430918 and 9521426. Classification of NM_000277.1(PAH):c.165T>G(F55L) 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 19, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000092734). A different missense change at the same codon (p.Phe55Ser) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120266). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 31, 2018	The PAH c.165T>G (p.Phe55Leu) missense variant has been reported in over nine studies and is found in at least twelve probands in a compound heterozygous state (Zekanowski et al. 1997; Bosco et al. 1998; Guldberg et al. 1998; Zekanowski et al. 2001; Muntau et al. 2002; Aulehla-Scholz et al. 2003; Bercovoch et al. 2008; Sarkissan et al. 2010; Zhu et al. 2013). The p.Phe55Leu variant was absent from 320 controls and is reported at a frequency of 0.00093 in the Latino population of the Genome Aggregation Database. Functional studies by Gertsing et al. (2008) demonstrated that the Phe55 residue is part of the hydrophobic core of the regulatory domain of the protein. The variant showed only a moderate reduction in enzyme activity compared to wild type and was shown to induce misfolding and facilitate unfolding but did not affect the conformational stability of the catalytic domain. Based on the evidence, the p.Phe55Leu 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	Mar 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 55 of the PAH protein (p.Phe55Leu). This variant is present in population databases (rs199475598, gnomAD 0.09%). This missense change has been observed in individual(s) with hyperphenylalaninemia or phenylketonuria (PMID: 9298832, 9521426, 10598814, 12501224, 18299955, 23932990). ClinVar contains an entry for this variant (Variation ID: 92734). 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: 18538294). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 26, 2022	The c.165T>G (p.Phe55Leu) variant in PAH has been reported in at least 27 individuals with phenylalanine hydroxylase deficiency/phenylketonuria (PKU)/hyperphenylalaninemia (HPA) (Zhu 2013 PMID: 23932990, Zekanowski PMID: 9298832,Vela-Amieva 2021 PMID: 34828281, Ozturk 2022 PMID: 35405047, Ferreira 2021 PMID: 33465300, Bosco 1998 PMID: 9521426, Bercovich 2008 PMID: 1829995, Aldamiz-Echevarria 2016 PMID: 27121329), and at least 12 of these individuals were compound heterozygous for a second pathogenic PAH variant. It has been identified in 0.002% of AMR chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID: 92734). Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to to determine pathogenecity. In vitro functional studies support an impact of p.Arg155His on protein function (Gersting S, et al. 2008 PMID: 18538294). This variant occurs in exon 2 of PAH where numerous pathogenic variants in PAH have been identified, including at the same residue (p.Phe55Ser). In summary, c.165T>G (p.Phe55Leu) meets criteria to be classified as pathogenic for autosomal recessive PKU. ACMG/AMP Criteria applied: PM3_VeryStrong, PM5_Strong, PM2_Supporting, PP3, PS3_Supporting. -

not provided

Pathogenic:2Other: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)	Aug 07, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	PAH: PM3:Very Strong, PM2, PS3:Supporting -

PAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

The PAH c.165T>G variant is predicted to result in the amino acid substitution p.Phe55Leu. This variant has previously been reported, in the compound heterozygous state with a second causative variant, in multiple patients with hyperphenylalaninemia (e.g., Zekanowski et al. 1997. PubMed ID: 9298832; Bosco et al. 1998. PubMed ID: 9521426; Aldámiz-Echevarría et al. 2016. PubMed ID: 27121329; Table S3, Hillert et al. 2020. PubMed ID: 32668217). In functional studies, the p.Phe55Leu substitution was reported to affect protein allostery and proteolytic stability (Gersting et al. 2008. PubMed ID: 18538294). This variant is typically associated with mild hyperphenylalaninemia or mild phenylketonuria (PKU) (Table S2, Hillert et al. 2020. PubMed ID: 32668217). This variant is classified as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/92734/). Taken together, we classify this variant as pathogenic. -

Hyperphenylalaninemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 30, 2016

Variant summary: The PAH c.165T>G (p.Phe55Leu) variant located in the ACT domain causes a missense change involving 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 11/121376 (1/11037), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest has been reported in multiple affected individuals diagnosed with HPA as compound heterozygotes. In addition, multiple databases and clinical diagnostic laboratories have cited the variant with a classification of "pathogenic" or "likely pathogenic." Therefore, the variant of interest has been classified as "Pathogenic." -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 13, 2020

ACMG classification criteria: PS3, PS4, PM3, PP1, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;D;D;D

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.0

M;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Pathogenic

0.85

Sift

Benign

0.096

T;T;D;D

Sift4G

Benign

0.12

T;T;D;.

Polyphen

0.89

P;.;.;.

Vest4

0.86

MutPred

0.86

Gain of ubiquitination at K50 (P = 0.1111);.;Gain of ubiquitination at K50 (P = 0.1111);Gain of ubiquitination at K50 (P = 0.1111);

MVP

0.98

MPC

0.22

ClinPred

0.68

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.86

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.

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