rs62642929

Positions:

chr12-102894776-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PS3PM3_Strong

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency: 0.00009 in gnomAD; PS3: 26% PAH enzyme activity; PM3_Strong: Detected with Y414C, pathogenic in ClinVar and V245L (P/LP) (PMID:9429153; PMID:24368688). 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: (PM2, PS3, PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229515/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:15O:1

Conservation

PhyloP100: 2.77

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:

PAH (HGNC:):

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.311C>A	p.Ala104Asp	missense_variant	3/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.311C>A	p.Ala104Asp	missense_variant	4/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.311C>A	p.Ala104Asp	missense_variant	3/7		XP_016874859.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.863-9922G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.311C>A	p.Ala104Asp	missense_variant	3/13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152124

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251446

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727222

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:

0.000150

Gnomad4 NFE exome

AF:

0.0000459

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74310

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 27, 2018	Variant summary: PAH c.311C>A (p.Ala104Asp) results in a non-conservative amino acid change located in the ACT domain 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 5.3e-05 in 246214 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (5.3e-05 vs 0.0079), allowing no conclusion about variant significance. c.311C>A has been reported in the literature in multiple individuals affected with mild PKU due to Phenylalanine Hydroxylase Deficiency (mild Phenylketonuria)(Zurfluh_2008, Bayat_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 10%-<30% of normal activity. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 104 of the PAH protein (p.Ala104Asp). This variant is present in population databases (rs62642929, gnomAD 0.009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 18299955, 22112818, 22526846, 23764561, 26666653). ClinVar contains an entry for this variant (Variation ID: 102650). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 07, 2018	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency: 0.00009 in gnomAD; PS3: 26% PAH enzyme activity; PM3_Strong: Detected with Y414C, pathogenic in ClinVar and V245L (P/LP) (PMID:9429153; PMID:24368688). 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: (PM2, PS3, PM3_Strong). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 11, 2019	Across a selection of the available literature, the PAH c.311C>A (p.Ala104Asp) missense variant has been identified in at least 12 individuals with phenylalanine hydroxylase deficiency (PAH), including in one in a homozygous state, and in 11 in a compound heterozygous state (Guldberg et al. 1995; Zekanowski et al. 1997; Pronina et al. 2003; Ho et al. 2014; Trunzo et al. 2015). The p.Ala104Asp variant is associated with a mild phenotype with the exception of one compound heterozygous individual who presented with the classical form. Control data are unavailable for this variant, which is reported at a frequency of 0.000089 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrated that the p.Ala104Asp PAH retained 26% of its activity but with a significantly reduced half-life of the aggregates compared to wild type PAH. In vitro, wild type PAH was comprised of tetramers and dimers, whereas mutant PAH was primarily dimeric with moderate amounts of aggregates, and significantly reduced amounts of tetramers (Waters et al. 1998). Additionally, hybrid expression models have shown a modest decrease in reporter activity as well as an increase in the rate of degradation in homomeric interactions for the p.Ala104Asp mutant as compared to wildtype (Waters et al. 2001). Based on the collective evidence, the p.Ala104Asp 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. -

not provided

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 01, 2023	PM2_moderate, PM3_strong, PS3 -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2024	Reported previously in the heterozygous state, in the presence of a second PAH variant, in association with phenylketonuria (PKU) (PMID: 1301187, 9429153, 12655551, 17627389, 24368688); Published functional studies found this variant is associated with reduced protein expression and catalytic activity (PMID: 9191407, 21953985); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Associated with tetrahydrobiopterin (BH4) responsiveness (PMID: 17935162); This variant is associated with the following publications: (PMID: 11461190, 10384369, 9792411, 22526846, 9429153, 24368688, 17627389, 23357515, 12655551, 30037505, 30648773, 31355225, 22112818, 18299955, 23764561, 26666653, 26542770, 23514811, 34426522, 32668217, 33101986, 32778825, 9191407, 1301187, 17935162, 21953985) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

PAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2024

The PAH c.311C>A variant is predicted to result in the amino acid substitution p.Ala104Asp. This variant has been reported in the homozygous state or with a second PAH variant in patients with phenylalanine hydroxylase deficiency, ranging from mild hyperphenylalaninemia to classic phenylketonuria (PKU) (e.g., Zekanowski et al. 1997. PubMed ID: 9429153; Bercovich et al. 2008. PubMed ID: 18299955; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Trunzo et al. 2015. PubMed ID: 26210745; Su et al. 2019. PubMed ID: 31355225; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). Based on functional studies, the p.Ala104Asp amino acid change has been reported to result in reduced PAH enzyme activity and has been classified as a BH4-responsive amino acid substitution (Zurflüh et al. 2008. PubMed ID: 17935162; Shi et al. 2012. PubMed ID: 21953985; Himmelreich et al. 2018. PubMed ID: 30037505). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD. It has been classified as pathogenic by multiple outside laboratories as well as the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/102650/). Based on these observations, we classify this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

T;T;T;T

Eigen

Benign

-0.19

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.38

T;T;T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.4

L;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Uncertain

0.61

Sift

Benign

0.65

T;T;T;D

Sift4G

Benign

0.54

T;T;T;.

Polyphen

0.0020

B;.;.;.

Vest4

0.89

MVP

0.97

MPC

0.039

ClinPred

0.14

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.94

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.

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