12-102843683-C-T

Position:

chr12-102843683-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS3PP4PP3PM3PM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low in ExAC and 1000 genomes (PMID:9860305); PS3: PAH activity in COS cell expression system 15% (PMID:9860305); PM3: Compound het with severe mutation (PMID:9860305); PP3: ; PP4: Reported in patient with classic PKU (PMID:9860305). 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, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251543/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

10

6

3

Clinical Significance

Pathogenic reviewed by expert panel P:13O:1

Conservation

PhyloP100: 5.04

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 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.

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.1162G>A	p.Val388Met	missense_variant	11/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.1162G>A	p.Val388Met	missense_variant	12/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1162G>A	p.Val388Met	missense_variant	11/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

7

AN:

151940

Hom.:

0

Cov.:

31

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000480

GnomAD3 exomes

AF:

0.0000836

AC:

21

AN:

251286

Hom.:

0

AF XY:

0.0000810

AC XY:

11

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

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:

0.0000440

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000363

AC:

53

AN:

1461564

Hom.:

0

Cov.:

30

AF XY:

0.0000344

AC XY:

25

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000461

AC:

7

AN:

151940

Hom.:

0

Cov.:

31

AF XY:

0.0000539

AC XY:

4

AN XY:

74208

show subpopulations

Gnomad4 AFR

AF:

0.0000726

Gnomad4 AMR

AF:

0.000196

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:

0.000480

Alfa

AF:

0.0000267

Hom.:

0

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.0000659

AC:

8

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 388 of the PAH protein (p.Val388Met). This variant is present in population databases (rs62516101, gnomAD 0.05%). This missense change has been observed in individual(s) with PKU (PMID: 7581408, 12655544, 17935162, 23500595, 23932990; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Spain and Portugal ancestry (PMID: 7581408, 7668259, 12655544, 17935162, 23500595, 23932990; Invitae). ClinVar contains an entry for this variant (Variation ID: 619). 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: 19036622, 21953985). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000619, PMID:8406445). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 9860305). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 9860305). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102541,VCV000120260, PMID:26666653,9452061). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.862>=0.6, 3CNET: 0.99>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000992). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 05, 2018	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low in ExAC and 1000 genomes (PMID:9860305); PS3: PAH activity in COS cell expression system 15% (PMID:9860305); PM3: Compound het with severe mutation (PMID:9860305); PP3: ; PP4: Reported in patient with classic PKU (PMID:9860305). 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, PP3, PP4). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 09, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 09, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2019	Variant summary: PAH c.1162G>A (p.Val388Met) results in a conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251286 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00041 vs 0.0079), allowing no conclusion about variant significance. The variant, c.1162G>A, has been reported in the literature in homozygous or compound heterozygous state in multiple individuals affected with mild or classic PKU (Dobrowolski_2011, Danecka_2015). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated variant proteins to have considerably reduced PAH activity compared to wild type (Dobrowolski_2011, Danecka_2015). Four submitters including one expert panel (ClinGen PAH Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

not provided

Pathogenic:2Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 12, 2021	Functional studies in the published literature indicate the variant exhibited 12-43% of normal enzyme activity (PMID: 7668259 (1995), 25596310 (2015), 24401910 (2014), 10767175 (2000), and is associated with a milder phenotype of PKU responsive to BH4 (PMID: 16504182 (2006), 17935162 (2008)). Based on the available information, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 10, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.30

D

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

25

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.77

D

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.98

D

MutationAssessor

Pathogenic

3.7

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

T

PROVEAN

Benign

-1.9

N;N

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.93

MVP

0.99

MPC

0.24

ClinPred

0.81

D

GERP RS

5.3

Varity_R

0.76

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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: rs62516101; hg19: chr12-103237461;