12-102840472-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP4_ModeratePM3

This summary comes from the ClinGen Evidence Repository: The c.1243G>A (p.Asp415Asn) variant in PAH has been reported in 3 patients with Hyperphenylalaninemia (BH4 deficiency excluded). (PP4_Moderate; PMID:1358789). This variant has an extremely low allele frequency (0.0001097 in gnomAD) (PM2; http://gnomad.broadinstitute.org). This variant was detected in trans with R408W, F39L, Y414C, IVS10-11G>A (Pathogenic in ClinVar) (PM3_Very-strong; PMID:1358789; PMID:12501224; PMID:18299955). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA114364/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:17O:1

Conservation

PhyloP100: 3.76

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.

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.1243G>A	p.Asp415Asn	missense_variant	Exon 12 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.1243G>A	p.Asp415Asn	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.1243G>A	p.Asp415Asn	missense_variant	Exon 12 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000882

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000107

AC:

AN:

251434

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

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:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000643

AC:

AN:

1461696

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000105

AC:

AN:

152016

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.0000917

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Dec 20, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000277.1(PAH):c.1243G>A(D415N) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and can be associated with variant or non-PKU hyperphenylalaninemia. Sources cited for classification include the following: PMID 1358789, 23500595, 24296287, 17935162, 12501224, 22513348, 9781015, 18299955, 18294361, 8088845 and 10234516. Classification of NM_000277.1(PAH):c.1243G>A(D415N) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 415 of the PAH protein (p.Asp415Asn). This variant is present in population databases (rs62644499, gnomAD 0.04%). This missense change has been observed in individual(s) with mild phenylketonuria or mild hyperphenylalaninemia (PMID: 1358789, 18299955, 23932990, 24296287). ClinVar contains an entry for this variant (Variation ID: 617). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PAH function (PMID: 17935162). For these reasons, this variant has been classified as Pathogenic. -

Aug 20, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of available literature, the PAH c.1243G>A (p.Asp415Asn) missense variant has been identified in a compound heterozygous state in 19 patients (Economou-Petersen et al. 1992; Guldberg et al. 1994; Guldberg et al. 1995; Bercovich et al. 2008; Trunzo et al. 2014; Ho et al. 2014; Jeannesson-Thivisol et al. 2015). The p.Asp415Asn variant was absent from 220 controls and is reported at a frequency of 0.000358 in the Latino population of the Genome Aggregation Database. In vivo analysis of phenylalanine loading demonstrates that affected individuals with the p.Asp415Asn variant in a compound heterozygous state with a null PAH variant were able to clear the dose in 24 hours, which was consistent with the disease phenotype, and was established in several individuals affected by PAH deficiency (Economou-Petersen et al. 1992; Guldberg et al. 1995). Based on the evidence, the p.Asp415Asn variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 07, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 12, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1243G>A (p.Asp415Asn) variant in PAH has been reported in 3 patients with Hyperphenylalaninemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 1358789). This variant has an extremely low allele frequency (0.0001097 in gnomAD) (PM2; http://gnomad.broadinstitute.org). This variant was detected in trans with R408W, F39L, Y414C, IVS10-11G>A (Pathogenic in ClinVar) (PM3_Very-strong; PMID: 1358789; PMID: 12501224; PMID: 18299955). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong -

Aug 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided

Pathogenic:5Other:1

Dec 15, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is known to be associated with hyperphenylalaninemia and mild PKU. It is associated with residual PAH expression and activity and has been reported as compound heterozygous in multiple individuals with BH4-responsive hyperphenylalaninemia or mild PKU (PMID: 30037505 (2018), 27469133 (2017), 26666653 (2015), 24296287 (2014), 23932990 (2013), 17935162 (2008), 9634518 (1998), 9399896 (1997)). -

Nov 17, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 25, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4_moderate, PM2_moderate, PM3_very_strong -

Jun 30, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in association with mild hyperphenylalaninemia (Economou-Petersen et al., 1992; Guldberg et al., 1994; Trunzo et al., 2014); Functional studies found that this variant is associated with approximately 35% enzyme activity compared to wild-type (Himmelreich et al., 2018); Associated with BH4 responsiveness (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 30037505, 17935162, 31980526, 29499199, 29749107, 12501224, 27264808, 8088845, 24296287, 8929956, 11161839, 8406445, 9634518, 1358789, 22513348, 23500595) -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Hyperphenylalaninemia

Pathogenic:2

Sep 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 04, 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.1243G>A (p.Asp415Asn) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 7/121346 control chromosomes at a frequency of 0.0000577, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant has been reported in numerous individuals in the literature affected with mild-pku and mild-hyperphenylalaninemia, and has been associated with BH4 responsiveness. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

PAH-related disorder

Pathogenic:1

Mar 11, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PAH c.1243G>A variant is predicted to result in the amino acid substitution p.Asp415Asn. This variant has been reported in the heterozygous state with a second PAH pathogenic variant in numerous patients with mild hyperphenylalaninemia (MHP) (e.g., Economou-Petersen et al. 1992. PubMed ID: 1358789; Guldberg et al. 1996. PubMed ID: 8929956; Zhu et al. 2013. PubMed ID: 23932990; Trunzo et al. 2014. PubMed ID: 24296287; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653). We have also observed this variant internally, in the homozygous or presumed compound heterozygous state with a second pathogenic variant, in five patients with a biochemical or clinical diagnosis of hyperphenylalaninemia. In functional studies, the p.Asp415Asn substitution has been reported to reduce enzyme activity, with the BioPKU database reporting an average residual enzyme activity of 72% (Zurflüh et al. 2008. PubMed ID: 17935162; Himmelreich et al. 2018. PubMed ID: 30037505; http://www.biopku.org/pah/result-details-pah.asp?ID=582). The c.1243G>A (p.Asp415Asn) has been classified as ‘Pathogenic’ by the ClinGen PAH Variant Curation Expert Panel, as well as by several other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/617/). Based on these observations, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.32

DEOGEN2

Uncertain

0.63

D;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Benign

-0.81

N;.

PrimateAI

Benign

0.40

PROVEAN

Benign

3.3

N;N

REVEL

Uncertain

0.57

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.010

B;.

Vest4

0.74

MutPred

0.90

Gain of methylation at R413 (P = 0.0949);.;

MVP

0.89

MPC

0.031

ClinPred

0.065

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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