NM_000277.3:c.805A>C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP4_ModeratePP3PM3

This summary comes from the ClinGen Evidence Repository: The c.805A>C (p.Ile269Leu) variant in PAH has been reported in multiple individuals with PAH deficiency, including non-PKU HPA (BH4 deficiency excluded). (PP4_Moderate; PMID10767174, PMID 2350059). This variant has an extremely low allele frequency in ExAC and gnomAD (PM2; ENF=0.00013). This variant was detected in trans with multiple known pathogenic variants: PMID 9521426: c.842+3G>C; PMID 10767174: R261X; PMID 14726806: E280K; PMID 21871829: IVS10-11G>A (PM3_Very-strong). Computational prediction tools and conservation analysis suggest this 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: PM3_Very-strong, PP4_Moderate, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229775/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:13O:1

Conservation

PhyloP100: 6.27

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 rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.805A>C	p.Ile269Leu	missense_variant	Exon 7 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.805A>C	p.Ile269Leu	missense_variant	Exon 8 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.805A>C	p.Ile269Leu	missense_variant	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000307000.7 link	c.790A>C	p.Ile264Leu	missense_variant	Exon 8 of 14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000549247.6 link	n.564A>C		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1 link	c.-36A>C		upstream_gene_variant		5		ENSP00000489230.1	A0A0U1RQY4

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251364

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

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:

0.000123

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000214

AC:

313

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

142

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

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:

0.000265

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000238

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:11

Jan 07, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 strong, PM2 moderate, PM3 very strong, PP3 supporting, PP4 moderate -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 269 of the PAH protein (p.Ile269Leu). This variant is present in population databases (rs62508692, gnomAD 0.02%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9521426, 14726806, 21871829, 23500595). ClinVar contains an entry for this variant (Variation ID: 102842). 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%. For these reasons, this variant has been classified as Pathogenic. -

Dec 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.805A>C (p.Ile269Leu) variant in PAH has been reported in multiple individuals with PAH deficiency, including non-PKU HPA (BH4 deficiency excluded). (PP4_Moderate; PMID10767174, PMID 2350059). This variant has an extremely low allele frequency in ExAC and gnomAD (PM2; ENF=0.00013). This variant was detected in trans with multiple known pathogenic variants: PMID 9521426: c.842+3G>C; PMID 10767174: R261X; PMID 14726806: E280K; PMID 21871829: IVS10-11G>A (PM3_Very-strong). Computational prediction tools and conservation analysis suggest this 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: PM3_Very-strong, PP4_Moderate, PM2, PP3. -

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 20, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.805A>C (p.Ile269Leu) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251364 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (9.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.805A>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency, including non-PKU hyperphenylalaninemia (e.g. Matalon_2004, Rivera_2011, Couce_2013, Reblova_2013). These data indicate that the variant is very likely to be associated with disease. In vitro studies demonstrated a moderate reduction in residual PAH activity (63%) as compared to wild type (Rivera_2011). Four ClinVar submitters including an expert panel (ClinGen PAH Variant Curation Expert Panel) (evaluation after 2014) cite the variant as pathogenic/likely pathogenic while, one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 25, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PAH c.805A>C (p.Ile269Leu) variant has been reported in three studies in which it is found in a total of five individuals, including one sibling pair, with non-phenylketonuria hyperphenylalaninemia (non-PKU HPA). The variant was found in four individuals in a compound heterozygous state and in one individual in cis with a second missense variant and in trans with a third missense variant (Bosco et al. 1998; Rivera et al. 2011; Reblova et al. 2013). Control data are unavailable for the p.Ile269Leu variant which is reported at a frequency of 0.000464 in the Other population of the Genome Aggregation Database. Leandro et al. (2001) showed that the p.Ile269Leu variant caused a moderate reduction in the specific activity of the PAH enzyme as compared to wild type, when expressed in a prokaryotic expression system. Based on the evidence, the p.Ile269Leu variant is classified as likely pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Nov 01, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000277.1(PAH):c.805A>C(I269L) is a missense variant classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the I269L variant can be associated with variant or non-PKU hyperphenylalaninemia. I269L has been observed in cases with relevant disease (PMID: 9521426, 14726806, 21871829, 23357515, 23942198, 24350308, 27121329). Functional assessments of this variant are available in the literature (Leandro_2001_(no PMID; article)). I269L has been observed in population frequency databases (gnomAD: AMR 0.02%). In summary, NM_000277.1(PAH):c.805A>C(I269L) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Dec 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2Other:1

May 01, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classified as responsive to tetrahydrobiopterin (BH4) therapy (PMID: 17935162); This variant is associated with the following publications: (PMID: 17924342, 10767174, 23357515, 34405919, 9521426, 17513426, 21871829, 23500595, 11708866, 14726806, 27121329, 32668217, 17935162, 9634518) -

Jun 12, 2015

Eurofins Ntd Llc (ga)

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

N;N

REVEL

Pathogenic

0.80

Sift

Benign

0.039

D;T

Sift4G

Benign

0.074

T;T

Polyphen

0.16

B;.

Vest4

0.88

MVP

0.94

MPC

0.20

ClinPred

0.15

GERP RS

5.7

Varity_R

0.86

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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