12-102840477-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4_ModeratePM2PP3PM3PS3

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PS3: In vitro expression of altered protein in COS cells produces severe decrease of PAH activity (<3%); PM2: Extremely low frequency. ExAC MAF=0.00012; PP4_Moderate: Detected in PKU patients, BH4 deficiency excluded; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.895; PM3: Detected with V388M (pathogenic) in 2 patients (PMID:9860305; PMID:21307867). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM2, PP4_Moderate, PP3, PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229414/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 0.933

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 rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.1238G>C	p.Arg413Pro	missense_variant	Exon 12 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.1238G>C	p.Arg413Pro	missense_variant	Exon 13 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.1238G>C	p.Arg413Pro	missense_variant	Exon 12 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251440

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135892

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:8

Sep 28, 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 proline, which is neutral and non-polar, at codon 413 of the PAH protein (p.Arg413Pro). This variant is present in population databases (rs79931499, gnomAD 0.006%). This missense change has been observed in individual(s) with PAH-related disease (PMID: 24401910, 27264808). ClinVar contains an entry for this variant (Variation ID: 592). 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: 17935162, 21953985). For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3+PM3_VeryStrong -

Aug 05, 2016

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.1238G>C (p.Arg413Pro) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools predicting a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency 1/121344, which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest was found in multiple affected individuals diagnosed with classic PKU via publications and has been indicated that it is predominantly observed in populations of Asian origin. In addition, publications indicated that the patients showed zero PAH activity. In addition, multiple databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." -

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PAH-specific ACMG/AMP criteria applied: PS3: In vitro expression of altered protein in COS cells produces severe decrease of PAH activity (<3%); PM2: Extremely low frequency. ExAC MAF=0.00012; PP4_Moderate: Detected in PKU patients, BH4 deficiency excluded; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.895; PM3: Detected with V388M (pathogenic) in 2 patients (PMID:9860305; PMID:21307867). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM2, PP4_Moderate, PP3, PM3). -

Mar 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:3Other:1

Nov 01, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_moderate, PM3, PS3 -

Feb 07, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 28, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies found this variant is associated with severely diminished or completely absent of PAH enzyme activity compared to wildtype, supporting a damaging effect (Himmelreich et al., 2018; Wang et al., 1991); 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; Classified as responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 14654665, 8051931, 27173423, 29413232, 34704413, 29499199, 24401910, 21953985, 1301187, 2006152, 27264808, 25750018, 8929956, 25550961, 10484807, 9048935, 29317692, 30221392, 31355225, 30747360, 30275481, 26322415, 21307867, 15319459, 9860305, 1998345, 33677757, 32668217, 32778825, 30037505, 35314707, 29353259, 35405047, 33161754, 17935162, 16253218) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.48

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

0.88

P;.

Vest4

0.94

MutPred

0.95

Loss of methylation at R413 (P = 0.0508);.;

MVP

0.94

MPC

0.26

ClinPred

0.99

GERP RS

-1.6

Varity_R

0.96

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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