rs62517205

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM3_StrongPP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The c.601C>T (p.His201Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID:16198137). This variant is at a ow frequency in controls (3.964e-6 in gnomAD; PM2). This variant was detected with known pathogenic variants IVS10nt546 (PMID:9521426) and R158Q (PMID:16198137; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229643/MONDO:0009861/006

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:7O:1

Conservation

PhyloP100: 10.0

Publications

6 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 8 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.

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.601C>T	p.His201Tyr	missense_variant	Exon 6 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.601C>T	p.His201Tyr	missense_variant	Exon 7 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.601C>T	p.His201Tyr	missense_variant	Exon 6 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.601C>T	p.His201Tyr	missense_variant	Exon 6 of 13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000549111.5 link	n.697C>T		non_coding_transcript_exon_variant	Exon 6 of 6	1
PAH	ENST00000307000.7 link	c.586C>T	p.His196Tyr	missense_variant	Exon 7 of 14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000551988.5 link	n.*38C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251344

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111884

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5

Mar 15, 2017

Counsyl

Significance:Likely pathogenic

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. -

Feb 02, 2024

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 tyrosine, which is neutral and polar, at codon 201 of the PAH protein (p.His201Tyr). This variant is present in population databases (rs62517205, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9521426, 10598814, 16198137, 23792259). 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: 102752). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Nov 10, 2019

ClinGen PAH Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.601C>T (p.His201Tyr) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 16198137). This variant is at a ow frequency in controls (3.964e-6 in gnomAD; PM2). This variant was detected with known pathogenic variants IVS10nt546 (PMID: 9521426) and R158Q (PMID: 16198137; PM3_strong). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong. -

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 18, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1Other:1

Feb 28, 2025

GeneDx

Significance: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; This variant is associated with the following publications: (PMID: 23357515, 23792259, 10598814, 35023679, 32668217, 9521426, 16198137) -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Hyperphenylalaninemia

Pathogenic:1

Apr 13, 2017

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PAH c.601C>T (p.His201Tyr) variant located in the Aromatic amino acid hydroxylase, C-terminal (via InterPro) involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a damaging outcome. Reblova_2013 indicates that the His201 plays a key role in forming a H-bond needed for stablization. This variant is absent in 121300 control chromosomes (ExAC). Multiple publications have cited the variant in affected compound heterozygote individuals, predominantly from Italy, with a mild HPA. Taken together, the variant of interest has been classified as "pathogenic." -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.5

L;.

PhyloP100

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Pathogenic

0.80

Sift

Benign

0.090

T;T

Sift4G

Benign

0.17

T;T

Polyphen

0.94

P;.

Vest4

0.96

MutPred

0.95

Gain of MoRF binding (P = 0.1663);.;

MVP

0.98

MPC

0.11

ClinPred

0.92

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.95

Mutation Taster

=1/99

disease causing (ClinVar)

(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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rs62517205

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