rs199475647

Positions:

chr12-102866615-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4_ModeratePM2PM3_Strong

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: ExAC MAF: 0.00012; PP4_Moderate: Detected in patients with PKU/HPA. BH4 deficiency excluded. (PMID:11244681; PMID:23942198); PM3_Strong: Detected with D145V, A403V (Pathogenic) (PMID:11244681; PMID:23942198). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229576/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:6O:1

Conservation

PhyloP100: 5.31

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 Likely_pathogenic. Variant got 8 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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.490A>G	p.Ile164Val	missense_variant	5/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.490A>G	p.Ile164Val	missense_variant	6/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.490A>G	p.Ile164Val	missense_variant	5/7		XP_016874859.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.807+1388T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.490A>G	p.Ile164Val	missense_variant	5/13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000549111.5 linkuse as main transcript	n.586A>G		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.475A>G	p.Ile159Val	missense_variant	6/14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000551988.5 linkuse as main transcript	n.530+10847A>G		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251370

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135848

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461522

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727090

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:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000287

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 164 of the PAH protein (p.Ile164Val). This variant is present in population databases (rs199475647, gnomAD 0.006%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 11244681, 23942198, 27121329; Invitae). 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: 102698). 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%. This variant disrupts the p.Ile164 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7833954, 9634518, 17502162, 26666653, 27578510). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 13, 2018	PAH-specific ACMG/AMP criteria applied: PM2: ExAC MAF: 0.00012; PP4_Moderate: Detected in patients with PKU/HPA. BH4 deficiency excluded. (PMID:11244681; PMID:23942198); PM3_Strong: Detected with D145V, A403V (Pathogenic) (PMID:11244681; PMID:23942198). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 17, 2023	- -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 30, 2021

ACMG classification criteria: PM2, PM3, PP4 -

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 27, 2023

Variant summary: PAH c.490A>G (p.Ile164Val) results in a conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) 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 1.6e-05 in 251370 control chromosomes (gnomAD). c.490A>G has been reported in the literature in the compound heterozygous state in multiple individuals affected with hyperphenylalaninemia/phenylketonuria (e.g. Mallolas_1999, Trujillano_2014, Wang_2018, Ferreira_2021) . These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including the ClinGen PAH Variant Curation Expert Panel, have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n=2) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.83

N;N

REVEL

Pathogenic

0.69

Sift

Benign

0.18

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.65

P;.

Vest4

0.81

MutPred

0.88

Gain of phosphorylation at Y168 (P = 0.0896);.;

MVP

0.95

MPC

0.047

ClinPred

0.60

GERP RS

6.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.45

gMVP

0.71

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