12-102852819-C-T

Position:

chr12-102852819-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000277.3(PAH):c.838G>A(p.Glu280Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E280A) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18O:1

Conservation

PhyloP100: 7.91

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 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-102852818-T-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 12-102852819-C-T is Pathogenic according to our data. Variant chr12-102852819-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102852819-C-T is described in Lovd as [Pathogenic]. Variant chr12-102852819-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.838G>A	p.Glu280Lys	missense_variant	7/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.838G>A	p.Glu280Lys	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.838G>A	p.Glu280Lys	missense_variant	7/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000307000.7 linkuse as main transcript	c.823G>A	p.Glu275Lys	missense_variant	8/14	5		ENSP00000303500
PAH	ENST00000549247.6 linkuse as main transcript	n.597G>A		non_coding_transcript_exon_variant	1/6	2
PAH	ENST00000635477.1 linkuse as main transcript			upstream_gene_variant		5		ENSP00000489230

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251278

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000168

AC:

245

AN:

1461742

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000208

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000262

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:

0.00

Alfa

AF:

0.0000981

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:11

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000580). The variant is in trans with the other variant. Different missense changes at the same codon (p.Glu280Gln, p.Glu280Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102864 , VCV000102866). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 280 of the PAH protein (p.Glu280Lys). This variant is present in population databases (rs62508698, gnomAD 0.008%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 2014036, 2564729, 12655546, 17935162, 23500595). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 580). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 2014036, 12655546, 17935162, 21953985). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2018	Variant summary: PAH c.838G>A (p.Glu280Lys) results in a conservative amino acid change located in the C-terminal domain of the Aromatic amino acid hydroxylase (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The c.838G>A variant has been reported in the literature in several individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) either in a homozygous state or in a compound heterozygosity with other HPA variants considered as pathogenic (e.g. Pey 2003, Kayaalp 1997, Couce 2013, Aldamiz-Echevarria 2016). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, concluding that the variant affected both folding and catalysis (Pey 2003). The most pronounced variant effect results in <10% of normal activity. One study reported absent/minimal BH4 responsiveness for patients carrying the variant (Couce 2013). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	NM_000277.1(PAH):c.838G>A(E280K) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 12655546, 11524738, 9781015, 17935162, 1971144, 23500595 and 2564729. Classification of NM_000277.1(PAH):c.838G>A(E280K) 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. -

not provided

Pathogenic:4Other:1

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 31, 2020	This variant was found in at least one symptomatic individual and predicted to have a damaging effect on the protein. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. It has also been reported to be associated with classic PKU and undetectable PAH enzyme activity (PMID: 12655546 (2003), 22763404(2012), 23500595 (2013), and 30963030 (2019)). -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 02, 2017	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2020	Published functional studies demonstrate that E280K is associated no detectable residual enzyme activity (Pey et al., 2003; Pey et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 2014036, 21953985, 30747360, 9399896, 1971144, 25087612, 22975760, 23500595, 17935162, 25750018, 2564729, 28676969, 29499199, 29317692, 12655546, 9101291, 30037505, 30963030, 31355225, 31589614, 33101986, 17924342, 32778825, 29288420, 33375644) -

PAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2024

The PAH c.838G>A variant is predicted to result in the amino acid substitution p.Glu280Lys. This is a commonly reported pathogenic variant that, in the homozygous state, has been associated with classic phenylketonuria (PKU) (e.g., Couce et al. 2013. PubMed ID: 23500595; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). The p.Glu280 amino acid has been reported to be located in the active site, and in functional assays the p.Glu280Lys substitution has essentially abolished PAH enzyme activity and resulted in a PAH protein that is non-responsive to BH4 (e.g., Pey et al. 2003. PubMed ID: 12655546; Zurflüh et al. 2008. PubMed ID: 17935162). Different substitutions of the same amino acid (p.Glu280Ala, p.Glu280Gly) have also been reported to be causative for phenylalanine hydroxylase deficiency (e.g., Aulehla-Scholz and Heilbronner. 2003. PubMed ID: 12655553; Song et al. 2005. PubMed ID: 16256386). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Multiple independent submitters to ClinVar have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/580). In summary, this variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.838G>A (p.E280K) alteration is located in coding exon 7 of the PAH gene. This alteration results from a G to A substitution at nucleotide position 838, causing the glutamic acid (E) at amino acid position 280 to be replaced by a lysine (K). The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the PAH c.838G>A alteration was observed in 0.006% (16/282,678) of total alleles studied, with a frequency of 0.008% (10/128,998) in the European (non-Finnish) subpopulation. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been reported homozygous or compound heterozygous with another mutation in PAH in multiple unrelated patients with phenylalanine hydroxylase (PAH) deficiency (Lyonnet, 1989; Okano, 1991; Su, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.E280 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Functional analysis demonstrated that the E280K alteration decreases PAH activity significantly compared to wild-type (Zurflüh, 2008; Shi, 2012). Three-dimensional structural analysis of the protein reveals that this alteration is an active site mutation (Pey, 2003). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.E280K alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Undiagnosed Diseases Network, NIH

Oct 27, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.8

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0040

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.96

MVP

0.99

MPC

0.25

ClinPred

0.89

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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