12-102855315-C-A

Position:

chr12-102855315-C-A

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PS3PM3PP4_Moderate

This summary comes from the ClinGen Evidence Repository: This c.527G>T (p.Arg176Leu) variant in PAH was reported in multiple patients with hyperphenylalaninemia and detected with 11 pathogenic variants (PMID:27121329, 9634518, and 29288420). Experimental studies from two publications have demonstrated this variant to have a deleterious effect (PMID:17924342 and 30037505). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PS3, and PP4_moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA114371/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:14O:1

Conservation

PhyloP100: 0.121

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 8 ACMG points.

PS3

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/exons	MANE	Protein
PAH	NM_000277.3 linkuse as main transcript	c.527G>T	p.Arg176Leu	missense_variant	6/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.527G>T	p.Arg176Leu	missense_variant	7/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.527G>T	p.Arg176Leu	missense_variant	6/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.527G>T	p.Arg176Leu	missense_variant	6/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5 linkuse as main transcript	n.623G>T		non_coding_transcript_exon_variant	6/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.512G>T	p.Arg171Leu	missense_variant	7/14	5		ENSP00000303500
PAH	ENST00000551988.5 linkuse as main transcript	n.548G>T		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000441

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

251160

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

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:

0.0000352

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000451

AC:

AN:

1461804

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000224

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:

0.0000405

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000959

Alfa

AF:

0.0000141

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 176 of the PAH protein (p.Arg176Leu). This variant is present in population databases (rs74486803, gnomAD 0.02%). This missense change has been observed in individual(s) with mild phenylketonuria, classical phenylketonuria and hyperphenylalaninemia (PMID: 8088845, 15464430, 17935162, 23500595, 27121329). ClinVar contains an entry for this variant (Variation ID: 631). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 17924342, 27121329). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 14, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 06, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Oct 16, 2020	This c.527G>T (p.Arg176Leu) variant in PAH was reported in multiple patients with hyperphenylalaninemia and detected with 11 pathogenic variants (PMID: 27121329, 9634518, and 29288420). Experimental studies from two publications have demonstrated this variant to have a deleterious effect (PMID: 17924342 and 30037505). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PS3, and PP4_moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -

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)	Jul 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2023	Considered a mild PAH variant as it is associated with significant residual phenylalanine hydroxylase enzyme activity and has been described in association with mild and moderate PKU and hyperphenylalaninemia (PMID: 17935162, 23500595, 8088845); This variant is associated with the following publications: (PMID: 25087612, 23500595, 34828281, 8088845, 26990548, 31623983, 29997390, 10234516, 27121329, 26210745, 30459323, 31589614, 32668217, 33465300, 29288420, 30037505, 17935162) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2021

The c.527G>T (p.R176L) alteration is located in exon 6 (coding exon 6) of the PAH gene. This alteration results from a G to T substitution at nucleotide position 527, causing the arginine (R) at amino acid position 176 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (15/282552) total alleles studied. This alteration has been reported in the compound heterozygous state with a second PAH alteration in several patients with hyperphenylalaninemia and has been reported as a BH4-responsive alteration (Guldberg, 1994; Zurflüh, 2008; Ohlsson, 2017; Aldámiz-Echevarría, 2016). In addition, another alteration at this position (p.R176Q) has also been reported in affected patients (Desviat, 1999; Aldámiz-Echevarría, 2016; Chen, 2018). This amino acid position is not well conserved in available vertebrate species. In vitro functional studies demonstrate reduced residual PAH enzyme activity in multiple cell systems (Gjetting, 2001; Himmelreich, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Hyperphenylalaninemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 1994

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Aug 16, 2021

ACMG classification criteria: PS3, PM3, PP4 -

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 02, 2020

Variant summary: PAH c.527G>T (p.Arg176Leu) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251160 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Hyperphenylalaninemia (5.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.527G>T has been reported in the literature in multiple individuals affected with Hyperphenylalaninemia (example Aldamiz-Echevarria_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal PAH activity (Aldamiz-Echevarria_2016). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.77

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Uncertain

0.62

Sift

Uncertain

0.029

D;D

Sift4G

Uncertain

0.047

D;T

Polyphen

0.0030

B;.

Vest4

0.60

MVP

0.88

MPC

0.037

ClinPred

0.93

GERP RS

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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