rs199475619

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3PP4PM3PM2

This summary comes from the ClinGen Evidence Repository: This c.157C>T (p.Arg53Cys) variant in PAH was reported in trans with pathogenic variant p.Arg158Gln in 1 patient with PAH deficiency (324 uMol/L Phe) (PMID:28982351). This variant was found at an amino acid residue where p.Arg53His, a missense variant of uncertain significance, has been seen before. Computational evidence for this missense variant supports a deleterious effect (REVEL=0.766). This variant is found at an extremely low frequency in gnomAD and ExAC (MAF=0.00012), and absent from 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229445/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:2O:1

Conservation

PhyloP100: 2.96

Publications

4 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: Likely_pathogenic. The variant received 6 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.

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
PAH	NM_000277.3 link	c.157C>T	p.Arg53Cys	missense_variant	Exon 2 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 link	c.157C>T	p.Arg53Cys	missense_variant	Exon 3 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.157C>T	p.Arg53Cys	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.157C>T	p.Arg53Cys	missense_variant	Exon 2 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251390

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000460

AC:

AN:

1456616

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

725060

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.000128

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

1107318

Other (OTH)

AF:

0.0000997

AC:

AN:

60202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

AF:

0.0000789

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41422

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.0000305

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:3Uncertain:1

Dec 28, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 28, 2023

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 53 of the PAH protein (p.Arg53Cys). This variant is present in population databases (rs199475619, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 28982351; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102600). 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%. For these reasons, this variant has been classified as Pathogenic. -

May 29, 2021

ClinGen PAH Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

This c.157C>T (p.Arg53Cys) variant in PAH was reported in trans with pathogenic variant p.Arg158Gln in 1 patient with PAH deficiency (324 uMol/L Phe) (PMID: 28982351). This variant was found at an amino acid residue where p.Arg53His, a missense variant of uncertain significance, has been seen before. Computational evidence for this missense variant supports a deleterious effect (REVEL=0.766). This variant is found at an extremely low frequency in gnomAD and ExAC (MAF=0.00012), and absent from 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4. -

not provided

Pathogenic:1Other:1

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 11, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in a child with mild hyperphenylalaninemia (Liu et al., 2017); This variant is associated with the following publications: (PMID: 29316886, 28982351, 17924342) -

PAH-related disorder

Pathogenic:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PAH c.157C>T variant is predicted to result in the amino acid substitution p.Arg53Cys. This variant has been reported in the compound heterozygous state in an individual(s) with PAH deficiency (PubMed ID: Liu N et al. 2017. PubMed ID: 28982351). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic by the ClinGen PAH Variant Curation Expert Panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/102600/). Taken together, we classify this variant as likely pathogenic. -

not specified

Uncertain:1

May 29, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PAH c.157C>T (p.Arg53Cys) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 3.2e-05 in 251390 control chromosomes. c.157C>T has been observed in compound heterozygous individual(s) affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)/Hyperphenylalaninemia (e.g. Liu_2017, internal data). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28982351). ClinVar contains an entry for this variant (Variation ID: 102600). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;D;D;D

Eigen

Benign

0.088

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.1

M;.;.;.

PhyloP100

3.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.9

D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;.

Polyphen

0.040

B;.;.;.

Vest4

0.79

MutPred

0.85

Gain of catalytic residue at L54 (P = 0.0174);.;Gain of catalytic residue at L54 (P = 0.0174);Gain of catalytic residue at L54 (P = 0.0174);

MVP

0.95

MPC

0.038

ClinPred

0.32

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.78

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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