rs78655458

Positions:

chr12-102852828-A-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP3PS3PM3PP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The c.829T>G (p.Tyr277Asp) variant in PAH has been reported in 2 individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID:8268925; PMID:23500595). This variant has an extremely low allele frequency (1/121400) in ExAC (PM2; http://exac.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with L48S (Pathogenic in ClinVar) (PM3; PMID:23500595). 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: PP4_Moderate, PS3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA251534/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

14

4

1

Clinical Significance

Pathogenic reviewed by expert panel P:13O:1

Conservation

PhyloP100: 7.52

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 Pathogenic. Variant got 11 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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.829T>G	p.Tyr277Asp	missense_variant	7/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.829T>G	p.Tyr277Asp	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.829T>G	p.Tyr277Asp	missense_variant	7/13	1	NM_000277.3	ENSP00000448059.1		P00439
PAH	ENST00000307000.7 link	c.814T>G	p.Tyr272Asp	missense_variant	8/14	5		ENSP00000303500.2		J3KND8
PAH	ENST00000549247.6 link	n.588T>G		non_coding_transcript_exon_variant	1/6	2
PAH	ENST00000635477.1 link	c.-12T>G		upstream_gene_variant		5		ENSP00000489230.1		A0A0U1RQY4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152188

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

4

AN:

251352

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

55

AN:

1461776

Hom.:

0

Cov.:

31

AF XY:

0.0000344

AC XY:

25

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152188

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000710

Hom.:

0

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Nov 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 06, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 10, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 05, 2017	Variant summary: The PAH c.829T>G (p.Tyr277Asp) variant involves the alteration of a conserved nucleotide located in the Aromatic amino acid hydroxylase, C-terminal domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/121400 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant has been reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2025	This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 277 of the PAH protein (p.Tyr277Asp). This variant is present in population databases (rs78655458, gnomAD 0.003%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 2035532, 8268925, 8632937, 12173030, 12655546, 23500595, 26666653). This variant is also known as c.754C>T. ClinVar contains an entry for this variant (Variation ID: 603). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 12655546). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 05, 2018	The c.829T>G (p.Tyr277Asp) variant in PAH has been reported in 2 individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8268925; PMID: 23500595). This variant has an extremely low allele frequency (1/121400) in ExAC (PM2; http://exac.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with L48S (Pathogenic in ClinVar) (PM3; PMID: 23500595). 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: PP4_Moderate, PS3 -

not provided

Pathogenic:3Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2020	Reported previously in association with both classic and moderate phenylketonuria (Labrune et al., 1991; Couce et al., 2013; Aldamiz-Echevarria et al., 2016); Functional studies in COS cells showed no residual enzyme activity compared to wild-type (Pey et al., 2003); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Response to BH4 therapy is inconsistent (Couce et al., 2013; Jeannesson-Thivisol et al., 2015; Aldamiz-Echevarria et al., 2016); This variant is associated with the following publications: (PMID: 18346471, 27413125, 12655546, 21953985, 25882749, 23500595, 27121329, 26666653, 2035532, 30037505, 31980526, 31589614, 32668217) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 05, 2016	- -

PAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2024

The PAH c.829T>G variant is predicted to result in the amino acid substitution p.Tyr277Asp. This variant has been reported, in homozygous state or in combination with a second pathogenic PAH variant, as causative for moderate or classic phenylketonuria (Pey et al. 2003. PubMed ID: 12655546; Sarkissian et al. 2012. PubMed ID: 23430918; Couce et al. 2013. PubMed ID: 23500595; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Table S1, Aldámiz-Echevarría et al. 2015. PubMed ID: 25882749; Hillert et al. 2020. PubMed ID: 32668217). It has been reported that the p.Tyr277 amino acid is near the active site of the enzyme, and functional studies of the p.Tyr277Asp variant have shown that this amino acid change completely abrogates the activity of the PAH enzyme (Pey et al. 2003. PubMed ID: 12655546; Shi et al. 2012. PubMed ID: 21953985). This variant has been interpreted as pathogenic by multiple outside laboratories, as well as the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/603/). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.50

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

27

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.73

D

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.95

D

MutationAssessor

Pathogenic

4.8

H;.

PrimateAI

Pathogenic

0.85

D

PROVEAN

Pathogenic

-9.6

D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

D;.

Vest4

0.96

MVP

0.99

MPC

0.29

ClinPred

1.0

D

GERP RS

4.6

Varity_R

0.94

gMVP

0.99

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.

Other links and lift over

dbSNP: rs78655458; hg19: chr12-103246606;