rs62514950

Positions:

chr12-102852848-C-T

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PM3PP4_ModeratePM2PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.809G>A (p.Arg270Lys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID:21871829, 23856132). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant has 11% residual PAH activity (PMID:27620137). This variant was detected with multiple pathogenic variants: IVS10nt-11G>A (2 patients), L348V, S349P, R158Q, E390G, D415N (PMID:21871829); and IVS4+5G>T (PMID:23856132). Computational prediction tools and conservation analysis 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, PM2, PP4_Moderate, PP3, PS3_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229781/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

15

3

1

Clinical Significance

Pathogenic reviewed by expert panel P:9O: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:

PAH (HGNC:):

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 8 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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.809G>A	p.Arg270Lys	missense_variant	7/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.809G>A	p.Arg270Lys	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.809G>A	p.Arg270Lys	missense_variant	7/13	1	NM_000277.3	ENSP00000448059.1		P00439
PAH	ENST00000307000.7 linkuse as main transcript	c.794G>A	p.Arg265Lys	missense_variant	8/14	5		ENSP00000303500.2		J3KND8
PAH	ENST00000549247.6 linkuse as main transcript	n.568G>A		non_coding_transcript_exon_variant	1/6	2
PAH	ENST00000635477.1 linkuse as main transcript	c.-32G>A		upstream_gene_variant		5		ENSP00000489230.1		A0A0U1RQY4

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD3 exomes

AF:

0.0000159

AC:

4

AN:

251348

Hom.:

0

AF XY:

0.00

AC XY:

0

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000752

AC:

11

AN:

1461842

Hom.:

0

Cov.:

31

AF XY:

0.00000825

AC XY:

6

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

32

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

0

ALSPAC

AF:

0.000259

AC:

1

ExAC

AF:

0.00000824

AC:

1

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 03, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAH function (PMID: 16545551, 17935162, 25453233, 27620137). 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. ClinVar contains an entry for this variant (Variation ID: 102846). This missense change has been observed in individual(s) with phenylketonuria and hyperphenylalaninemia (PMID: 12173030, 20082265, 20187763, 23500595, 23856132). This variant is present in population databases (rs62514950, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 270 of the PAH protein (p.Arg270Lys). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 26, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jun 08, 2020	The c.809G>A (p.Arg270Lys) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 21871829, 23856132). This variant has an extremely low allele frequency (MAF=0.00016) in gnomAD. This variant has 11% residual PAH activity (PMID: 27620137). This variant was detected with multiple pathogenic variants: IVS10nt-11G>A (2 patients), L348V, S349P, R158Q, E390G, D415N (PMID: 21871829); and IVS4+5G>T (PMID: 23856132). Computational prediction tools and conservation analysis 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, PM2, PP4_Moderate, PP3, PS3_supporting. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 06, 2020	- -

not provided

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2022	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; This variant is associated with the following publications: (PMID: 8528673, 11180595, 20082265, 20187763, 23856132, 29749107, 34828281, 17935162, 25750018, 27620137, 9598724, 7914195, 12173030, 16545551, 25453233, 23500595, 21871829, 26666653, 31355225, 32778825, 33465300) -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 25, 2022	The variant has been reported in multiple individuals largely affected with classic PKU when another severe disease-causing variant is present on the other allele (PMID: 20082265 (2010), 21871829 (2011), 23856132 (2013), 26666653 (2015), 33465300 (2021)). Functional studies have shown that this variant causes severely reduced activity ranging from 2.1 to 11% of the wild-type activity (PMID: 16545551 (2006), 27620137 (2016)). Based on the available information, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.59

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.93

D

MutationAssessor

Pathogenic

4.9

H;.

PrimateAI

Pathogenic

0.83

D

PROVEAN

Uncertain

-2.9

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.95

MutPred

0.99

Gain of methylation at R270 (P = 0.01);.;

MVP

0.99

MPC

0.24

ClinPred

1.0

D

GERP RS

5.7

Varity_R

0.98

gMVP

0.99

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: rs62514950; hg19: chr12-103246626; COSMIC: COSV100187900; COSMIC: COSV100187900;