rs62642940

Positions:

chr12-102846923-G-T

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PM3PM2_SupportingPP3PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000277.1(PAH):c.941C>A (p.Pro314His) variant is a missense variant in exon 9/13 of PAH. It has been found to result in 15% of wild-type PAH enzyme activity in a standard cDNA system and 5% of wild-type PAH enzyme activity in an Intinc system (PMID:18590700) (PS3_supporting). It has been noted in at least five patients, including in trans with Pathogenic or Likely Pathogenic variants and among those whom BH4 deficiency had been excluded (PM3_VeryStrong (4.25 points total); PP4_Moderate). It has been previously reported in a Mexican patient with mild hyperphenylalanemia in trans with the c.809G>A (p.Arg270Lys) variant (Pathogenic in ClinVar) (PMID:24941924). It has been noted in 3 PKU patients: one in trans with the p.I94del variant (unclassified) and in two in trans with the p.Y277D variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID:23842451). It has been found in a patient with mild hyperphenylalanemia (plasma Phe 456 umol/L) and BH4 deficiency excluded, in trans with the p.R155H variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID:28593914). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.91) (PP3).Classification: PathogenicSupporting Criteria: PS3_supporting; PM2_supporting; PM3_VeryStrong; PP4_Moderate; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229867/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8O:1

Conservation

PhyloP100: 9.60

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 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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.941C>A	p.Pro314His	missense_variant	9/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.941C>A	p.Pro314His	missense_variant	10/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.941C>A	p.Pro314His	missense_variant	9/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461466

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2019	Variant summary: PAH c.941C>A (p.Pro314His) results in a non-conservative amino acid change located in the catalytic domain (IPR041912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes (gnomAD). c.941C>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Guldberg_1998, Anjema_2013, Vela-Amieva_2015). These data indicate that the variant is very likely to be associated with disease. A publication reported experimental evidence using an in vitro expression system, and demonstrated that the variant significantly reduced enzyme activity, as well as (in addition to its protein level effects) it also increased exon 9 skipping by disrupting exonic splicing enhancer (ESE) motifs (Ho_2008). Two ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2023	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 expected to disrupt PAH protein function. This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 314 of the PAH protein (p.Pro314His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 8807319). ClinVar contains an entry for this variant (Variation ID: 102907). Experimental studies have shown that this missense change affects PAH function (PMID: 18590700). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Pro314 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24401910, 28982351, 29390883). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jan 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 12, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 30, 2023	The NM_000277.1(PAH):c.941C>A (p.Pro314His) variant is a missense variant in exon 9/13 of PAH. It has been found to result in 15% of wild-type PAH enzyme activity in a standard cDNA system and 5% of wild-type PAH enzyme activity in an Intinc system (PMID: 18590700) (PS3_supporting). It has been noted in at least five patients, including in trans with Pathogenic or Likely Pathogenic variants and among those whom BH4 deficiency had been excluded (PM3_VeryStrong (4.25 points total); PP4_Moderate). It has been previously reported in a Mexican patient with mild hyperphenylalanemia in trans with the c.809G>A (p.Arg270Lys) variant (Pathogenic in ClinVar) (PMID: 24941924). It has been noted in 3 PKU patients: one in trans with the p.I94del variant (unclassified) and in two in trans with the p.Y277D variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 23842451). It has been found in a patient with mild hyperphenylalanemia (plasma Phe 456 umol/L) and BH4 deficiency excluded, in trans with the p.R155H variant (Pathogenic in ClinVar and per ClinGen PAH VCEP) (PMID: 28593914). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2_supporting). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.91) (PP3). Classification: Pathogenic Supporting Criteria: PS3_supporting; PM2_supporting; PM3_VeryStrong; PP4_Moderate; PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 05, 2019	- -

not provided

Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.4

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.77

MutPred

0.85

Gain of catalytic residue at D315 (P = 0.087);.;

MVP

0.99

MPC

0.25

ClinPred

0.99

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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