rs118092776

Positions:

chr12-102912801-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. BS1PM3PP4_Moderate

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:8B:5O:1

Conservation

PhyloP100: 3.51

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 Uncertain_significance. Variant got 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/exons	MANE	Protein
PAH	NM_000277.3 linkuse as main transcript	c.158G>A	p.Arg53His	missense_variant	2/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.158G>A	p.Arg53His	missense_variant	3/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.158G>A	p.Arg53His	missense_variant	2/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.158G>A	p.Arg53His	missense_variant	2/13	1	NM_000277.3	ENSP00000448059	P1

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

GnomAD3 exomes

AF:

0.00168

AC:

422

AN:

251382

Hom.:

AF XY:

0.00164

AC XY:

223

AN XY:

135854

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 SAS exome

AF:

0.00147

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

Gnomad4 AFR exome

AF:

0.000330

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.000575

Gnomad4 EAS exome

AF:

0.0329

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.000705

Gnomad4 OTH exome

AF:

0.000681

GnomAD4 genome

AF:

0.00128

AC:

195

AN:

152260

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0201

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00143

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:8Benign:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Uncertain:6Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	-	PM3_VS+PP3+PP4+BS1 -
Likely benign, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 10, 2018	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2022	- -

not provided

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2024	Reported primarily in association with a mild hyperphenylalaninemia (HPA) phenotype (PMID: 27173423, 23764561, 26322415, 23932990); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -

PAH-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2023

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

Benign, criteria provided, single submitter

clinical testing

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

Feb 24, 2022

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

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;.;.;.

MutationTaster

Benign

1.0

D;D

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

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