12-102840414-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PS3_SupportingPP4_ModeratePP3PM2_SupportingPM3

This summary comes from the ClinGen Evidence Repository: The c.1301C>A (p.Ala434Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). PMID:16256386, 21147011). This variant is absent in population databases. Residual enzyme activity of the p.A434D mutant is 21.7% of wild type, and the formation and stability of the PAH protein was affected (PMID:18247293). This variant was detected with pathogenic variants: p.R252Q, p.R243Q (PMID:16256386); p.E390G, p.R261Q (PMID:21147011); p.R243Q (3 patients); IVS4-1G>A (2 patients); p.E280K, p.R111X (PMID:23932990). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PS3_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229427/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PAH
NM_000277.3 missense

Scores

11

7

1

Clinical Significance

Pathogenic reviewed by expert panel P:6O:1

Conservation

PhyloP100: 9.46

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 7 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.1301C>A	p.Ala434Asp	missense_variant	Exon 12 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.1301C>A	p.Ala434Asp	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.1301C>A	p.Ala434Asp	missense_variant	Exon 12 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

0

AN:

1459908

Hom.:

0

Cov.:

30

AF XY:

0.00

AC XY:

0

AN XY:

726370

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:6

Nov 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2023

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1301C>A (p.Ala434Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). PMID: 16256386, 21147011). This variant is absent in population databases. Residual enzyme activity of the p.A434D mutant is 21.7% of wild type, and the formation and stability of the PAH protein was affected (PMID: 18247293). This variant was detected with pathogenic variants: p.R252Q, p.R243Q (PMID: 16256386); p.E390G, p.R261Q (PMID: 21147011); p.R243Q (3 patients); IVS4-1G>A (2 patients); p.E280K, p.R111X (PMID: 23932990). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PS3_supporting, PM2_supporting, PP3. -

Jul 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 434 of the PAH protein (p.Ala434Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 16256386, 18247293, 24401910, 27264808, 29499199). ClinVar contains an entry for this variant (Variation ID: 102586). 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: 30037505). For these reasons, this variant has been classified as Pathogenic. -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Supporting+PM3_VeryStrong -

Jul 29, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 13, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided

Other:1

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.56

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

30

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.69

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Uncertain

0.66

T

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

1.0

D;.

Vest4

0.98

MutPred

0.94

Gain of disorder (P = 0.0763);.;

MVP

1.0

MPC

0.28

ClinPred

1.0

D

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.95

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: rs199475659; hg19: chr12-103234192;