12-102912801-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM3PP4_ModerateBS1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes); PP4_moderate: Detected in multiple patients with hyperphenylalaninemia, BH4 deficiency excluded (PMID:24401910, 26322415); PM3: Detected in trans with pathogenic variant p.R243Q. In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, PP4_moderate, PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229447/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 30 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:10B:5O:1

Conservation

PhyloP100: 3.51

Publications

68 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM3

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

PP4

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

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PAH	NM_000277.3 link	c.158G>A	p.Arg53His	missense_variant	Exon 2 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 link	c.158G>A	p.Arg53His	missense_variant	Exon 3 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.158G>A	p.Arg53His	missense_variant	Exon 2 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.158G>A	p.Arg53His	missense_variant	Exon 2 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0200

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00168

AC:

422

AN:

251382

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.0138

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.000677

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00159

AC:

2315

AN:

1456552

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1118

AN XY:

725058

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

33376

American (AMR)

AF:

0.000850

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000575

AC:

AN:

26092

East Asian (EAS)

AF:

0.0329

AC:

1302

AN:

39612

South Asian (SAS)

AF:

0.00133

AC:

115

AN:

86162

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000705

AC:

781

AN:

1107246

Other (OTH)

AF:

0.000681

AC:

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

107

214

322

429

536

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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

AF:

0.00128

AC:

195

AN:

152260

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41550

American (AMR)

AF:

0.00203

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0201

AC:

104

AN:

5182

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00156

Hom.:

Bravo

AF:

0.00150

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00175

AC:

212

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10Benign:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Uncertain:8Benign:4

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

PM3_VS+PP3+PP4+BS1 -

Jun 07, 2017

SingHealth Duke-NUS Institute of Precision Medicine

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:curation

- -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

- -

Jan 06, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1+PM3+PP4+PP3_Moderate -

May 18, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Aug 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01596 in ExAC (138/8648) and 0.0104 in gnomAD (265/18868 with 3 homozygotes); PP4: Detected in a patient with mild hyperphe (PMID:24401910); PM3: Detected with V388L (LP) (PMID:24401910). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, PP4, PM3). -

Nov 08, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Other:1

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 02, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported primarily in association with a mild hyperphenylalaninemia (HPA) phenotype (PMID: 27173423, 23764561, 26322415, 23932990); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30747360, 17924342, 25087612, 27264808, 26666653, 28676969, 34704413, 20981092, 24082139, 26521805, 23764561, 26322415, 9452061, 17935162, 23932990, 29653233, 29499199, 29032371, 30512147, 30459323, 28982351, 29454221, 30050108, 29390883, 29353259, 24401910, 30945278, 31355225, 30275481, 34426522, 33465300, 35193651, 35095998, 35405047, 33161754, 36537053, 16253218, 34405919, 34662886, 36646061, 36845377, 36577126, 32668217, 32778825, 36246604, 27173423, 38105685, 38784038) -

PAH-related disorder

Uncertain:1

Mar 03, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PAH c.158G>A variant is predicted to result in the amino acid substitution p.Arg53His. This variant has been documented as a common PAH variant in the Chinese population, and has been associated with mild hyperphenylalanemia (mHPA) (Park et al. 1998. PubMed ID: 9452061; Song et al. 2005. PubMed ID: 16256386; Liang et al. 2014 PubMed ID: 24401910; Lin et al. 2019. PubMed ID: 30904546). In a recent study of individuals identified by newborn genetic screening, 16 patients were identified with mildly elevated phenylalanine and the c.158G>A (p.Arg53His) variant on the opposite allele (in trans) from a pathogenic or likely pathogenic PAH variant (Huang et al. 2022. PubMed ID: 35193651). It should be noted that this particular variant has been reported to have an allele frequency of >1% in eastern Asian populations, including 3 homozygous individuals (http://gnomad.broadinstitute.org/variant/12-103306579-C-T) and has been suggested to be a likely benign variant based on higher allele frequencies in East Asian populations (Choi et al. 2017. PubMed ID: 29032371). While these higher allele frequencies would normally be considered too common for a recessive, pathogenic variant, the p.Arg53His amino acid change has been shown to only decrease the activity of the PAH protein to ~80% of wild-type (Liang et al. 2014. PubMed ID: 24401910). Such a modest effect on protein activity and the mild clinical phenotype associated with this variant may be consistent with this somewhat high allele frequency, and it is possible this variant may be causative for MHPA but is less likely to be causative for mild to classic phenylketonuria. This variant is currently interpreted as benign, likely benign, or uncertain in the ClinVar database, with the PAH Variant Curation Expert Panel interpreting it as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/102601/). Based on the collective evidence, we also interpret the clinical significance of this variant as uncertain. -

not specified

Benign:1

Feb 24, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PAH c.158G>A (p.Arg53His) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251382 control chromosomes (gnomAD), predominantly at a frequency of 0.014 within the East Asian subpopulation in the gnomAD database, including 3 homozygotes. Ten homozygotes for c.158G>A have also been reported in individuals from the general Japanese population (Yamaguchi-Kabata_2019). The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.158G>A has been reported in the literature in (mostly East Asian) individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and hyperphenylalaninemia (HPA) without strong evidence for causality (e.g. Park_1998, Liang_2014, Tao_2015, Zong_2018, Kuznetkova_2019, Lin_2019, Su_2019), with one report showing no clinical symptoms or signs of disease in 6 compound heterozygous patients identified during newborn screening and 1 homozygous parent, all of whom had blood Phe within the normal range while on a normal diet (e.g. Choi_2017). In multiple patients, the variant was reported in cis with another variant cited as pathogenic in ClinVar (e.g. Tao_2015, Odagiri_2021). In addition, the variant has been reported to co-occur with other pathogenic variants in PAH in individuals with PKU or HPA who were genotyped as either homozygotes or compound heterozygotes for other pathogenic variants that would be likely to explain the phenotype (e.g. Su_2019, Odagiri_2021). At least one publication reports experimental evidence evaluating an impact on protein function, where the variant protein had 79% enzymatic activity relative to the wild type control (Liang_2014). Nine ClinVar submitters have assessed the variant since 2014: five have classified the variant as of uncertain significance, two as likely benign, and two as benign. Based on the evidence outlined above, the variant was classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.041

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;D;D;D

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

T;T;T;T

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.2

M;.;.;.

PhyloP100

3.5

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.2

N;N;D;D

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0070

D;D;T;T

Sift4G

Uncertain

0.0060

D;D;D;.

Polyphen

0.88

P;.;.;.

Vest4

0.55

MVP

0.99

MPC

0.035

ClinPred

0.086

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.73

Mutation Taster

=52/48

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over