NM_000277.3:c.529G>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP3PM2PP4_ModeratePM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.529G>A (p.Val177Met) variant in PAH was detected in a patient with Mild hyperphenylalaninemia (BH4 deficiency ruled out). PMID:12501224 It has been detected with known pathogenic variants R408W (PMID:12501224), and IVS12+1G>A (PMID:23764561). It is absent from 1000G, ESP, and gnomAD; and at extremely low frequency in ExAC (MAF=0.00003). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.89. A different pathogenic missense change has been seen at this amino acid (V177L). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229609/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 1 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 3.39

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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.

PM5

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.529G>A	p.Val177Met	missense_variant	Exon 6 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.529G>A	p.Val177Met	missense_variant	Exon 7 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.529G>A	p.Val177Met	missense_variant	Exon 6 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.529G>A	p.Val177Met	missense_variant	Exon 6 of 13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000549111.5 link	n.625G>A		non_coding_transcript_exon_variant	Exon 6 of 6	1
PAH	ENST00000307000.7 link	c.514G>A	p.Val172Met	missense_variant	Exon 7 of 14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000551988.5 link	n.550G>A		non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

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:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251188

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000717

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:8

Dec 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.529G>A (p.Val177Met) variant in PAH was detected in a patient with Mild hyperphenylalaninemia (BH4 deficiency ruled out). PMID: 12501224 It has been detected with known pathogenic variants R408W (PMID: 12501224), and IVS12+1G>A (PMID: 23764561). It is absent from 1000G, ESP, and gnomAD; and at extremely low frequency in ExAC (MAF=0.00003). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.89. A different pathogenic missense change has been seen at this amino acid (V177L). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 177 of the PAH protein (p.Val177Met). This variant is present in population databases (rs199475602, gnomAD 0.003%). This missense change has been observed in individual(s) with mild hyperphenylalaninemia (PMID: 12501224, 17096675, 23430547, 23500595, 23764561, 27121329). ClinVar contains an entry for this variant (Variation ID: 102726). 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%. This variant disrupts the p.Val177 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8659548, 21445337, 22526846). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 18, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided

Pathogenic:2Other:1

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 03, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified as responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh MR et al., 2008; Leuret O et al., 2012); This variant is associated with the following publications: (PMID: 12649065, 23500595, 12501224, 17924342, 23430547, 17096675, 23764561, 34426522, 31589614, 35405047, 17935162, 22388642, 27121329) -

Oct 01, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PAH c.529G>A (p.Val177Met) variant has been reported in the published literature as heterozygous or compound heterozygous along with another pathogenic variant in several individuals with mild Hyperphenylalaninemia (PMID: 35405047 (2022), 27121329 (2016), 23430547 (2013), 23500595 (2013), 23764561 (2013), 17096675 (2007), 12501224 (2002)). Another variant at the same amino acid position, c.529G>C (p.Val177Leu), has been reported in individuals with Hyperphenylalaninemia (PMID: 8659548 (1996), 22526846 (2013)) and described as pathogenic in online databases (ClinVar https://www.ncbi.nlm.nih.gov/clinvar). The frequency of this variant in the general population, 0.000031 (4/128966 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

PAH-related disorder

Pathogenic:1

Jul 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PAH c.529G>A variant is predicted to result in the amino acid substitution p.Val177Met. This variant has been reported in individuals with mild hyperphenylalaninemia (see for example Muntau et al. 2002. PubMed ID: 12501224; Daniele et al. 2006. PubMed ID: 17096675; Djordjevic et al. 2012. PubMed ID: 23430547; Polak et al. 2013. PubMed ID: 23764561; Aldámiz-Echevarría et al. 2016. PubMed ID: 27121329). Alternative nucleotide substitutions at this amino acid position, including c.529G>C (p.Val177Leu) and c.530T>C (p.Val177Ala), have also been reported to be causative for phenylalanine hydroxylase deficiency (p.Val177Leu in Guldberg et al. 1996. PubMed ID: 8659548 and p.Val177Ala in Jennings et al. 2000. PubMed ID: 10980574). In ClinVar, the c.529G>A (p.Val177Met) variant is interpreted as pathogenic. This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Hyperphenylalaninemia

Pathogenic:1

Aug 04, 2016

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.529G>A (p.Val177Met) variant is located in the catalytic domain and causes a missense change involving a conserved nucleotide with 4/5 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 2/120722 (1/60361), 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 as a compound heterozygote, predominanlty in patients with mild hyperphenylalaninemia. A database cites the variant, however, with no classification being provided. Furthermore, another variant at this position, V177L (c.529G>C), has been reported as a pathogenic variant, as well. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.8

H;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-2.6

D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.027

D;D

Polyphen

0.99

D;.

Vest4

0.78

MutPred

0.95

Gain of disorder (P = 0.0559);.;

MVP

0.98

MPC

0.14

ClinPred

0.99

GERP RS

4.8

Varity_R

0.85

gMVP

0.91

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