12-102866597-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP4PP3PS3PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.508C>G (p.His170Asp) variant in PAH has been reported in 1 patient with hyperphenylalaninemia, and 1 patient with benign persistent hyperphenylalaninemia. (PP4; PMID:11385716). This variant has an extremely low allele frequency (0.00018) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 43% enzyme activity (PS3; PMID:17935162). This variant was detected in trans with R261X, c.60+5G>T, c.1315+1G>A (Pathogenic in ClinVar) (PM3_Strong; PMID:11385716; PMID:24941924). Computational prediction tools and conservation analysis suggest that the c.829T>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: PS3, PM3_Strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA273111/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense, splice_region

Scores

Splicing: ADA: 0.9920

Clinical Significance

Pathogenic reviewed by expert panel P:6O:1

Conservation

PhyloP100: 6.65

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:

LOC124902999 (HGNC:):

LOC124902999 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

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.508C>G	p.His170Asp	missense_variant, splice_region_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.508C>G	p.His170Asp	missense_variant, splice_region_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.508C>G	p.His170Asp	missense_variant, splice_region_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.807+1370G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.508C>G	p.His170Asp	missense_variant, splice_region_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000549111.5 link	n.604C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7 link	c.493C>G	p.His165Asp	missense_variant, splice_region_variant	Exon 6 of 14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000551988.5 link	n.530+10865C>G		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251354

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135838

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459932

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726424

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:4

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 170 of the PAH protein (p.His170Asp). This variant is present in population databases (rs199475655, gnomAD 0.01%). This missense change has been observed in individual(s) with benign persistent hyperphenylalaninemia and hyperphenylalaninemia (PMID: 11385716, 12971421). ClinVar contains an entry for this variant (Variation ID: 92744). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PAH function (PMID: 15557004, 17935162). For these reasons, this variant has been classified as Pathogenic. -

Jan 16, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.508C>G (p.His170Asp) variant in PAH has been reported in 1 patient with hyperphenylalaninemia, and 1 patient with benign persistent hyperphenylalaninemia. (PP4; PMID: 11385716). This variant has an extremely low allele frequency (0.00018) in gnomAD (PM2; http://gnomad.broadinstitute.org). This variant has 43% enzyme activity (PS3; PMID: 17935162). This variant was detected in trans with R261X, c.60+5G>T, c.1315+1G>A (Pathogenic in ClinVar) (PM3_Strong; PMID: 11385716; PMID: 24941924). Computational prediction tools and conservation analysis suggest that the c.829T>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: PS3, PM3_Strong -

not provided

Pathogenic:2Other:1

Aug 14, 2013

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

- -

Sep 24, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The H170D missense variants in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The H170D has been reported previously in association with both mild phenylketonuria (PKU) and with hyperphenylalaninemia (Yang et al., 2001; Vela-Amieva et al., 2015). Functional analysis found that H170D is associated with significant residual enzyme activity and is classified as a BH4-responsive variant (Zurfluh et al. 2008). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.7

H;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;.

Vest4

0.82

MutPred

0.95

Loss of MoRF binding (P = 0.0635);.;

MVP

0.99

MPC

0.27

ClinPred

0.98

GERP RS

6.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.86

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.84

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