rs199475655

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP4PP3PS3PM3_StrongPM2

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:7O:1

Conservation

PhyloP100: 6.65

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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.:

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251354

AF XY:

0.0000147

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 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

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.000134

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110280

Other (OTH)

AF:

0.00

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5

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 -

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

- -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 12, 2025

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.508C>G (p.His170Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2e-05 in 251354 control chromosomes. c.508C>G has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Yang_2001, Vela-Amieva_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Zurfluh_2008). The most pronounced variant effect results in 43% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 32668217, 24941924, 11385716, 17935162). ClinVar contains an entry for this variant (Variation ID: 92744). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2Other:1

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). -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 14, 2013

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

6.6

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

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.84

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over