rs398123292

Positions:

chr12-102877548-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PP4_ModeratePM3_Strong

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID 12655554) (PMID:21147011; PMID:12655554); PP4_Moderate: BH4 deficiency excluded (PMID:21147011). 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: (PP3, PM3_Strong, PP4_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220582/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 3 hom. )

Consequence

PAH
NM_000277.3 missense, splice_region

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:13U:1

Conservation

PhyloP100: 9.18

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 7 ACMG points.

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.355C>T	p.Pro119Ser	missense_variant, splice_region_variant	4/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.355C>T	p.Pro119Ser	missense_variant, splice_region_variant	5/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.355C>T	p.Pro119Ser	missense_variant, splice_region_variant	4/7		XP_016874859.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.808-2331G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.355C>T	p.Pro119Ser	missense_variant, splice_region_variant	4/13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152146

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:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000286

AC:

AN:

251358

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

135856

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:

0.00229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000140

AC:

204

AN:

1459698

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

148

AN XY:

726300

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:

0.00226

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74460

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:

0.00187

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00000912

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000346

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:13Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 26, 2021	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jul 29, 2018	PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID 12655554) (PMID:21147011; PMID:12655554); PP4_Moderate: BH4 deficiency excluded (PMID:21147011). 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: (PP3, PM3_Strong, PP4_Moderate). -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Sep 10, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 119 of the PAH protein (p.Pro119Ser). This variant is present in population databases (rs398123292, gnomAD 0.2%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 12655554, 21147011, 30389586, 31355225). ClinVar contains an entry for this variant (Variation ID: 92741). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 08, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (72 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a moderate amino acid change. (SP) 0600 - Variant is located in the annotated Biopterin_H domain (DECIPHER). (I) 0708 - Another missense variants comparable to the one identified in this case has conflicting previous evidence for pathogenicity. p.(Pro199Leu) has been reported in ClinVar once as a variant of unknown significance and once as likely pathogenic. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported eight times in ClinVar as pathogenic or likely pathogenic and reviewed by the ClinGen expert panel as likely pathogenic. This variant likely represents a hypomorphic allele as it has only been observed in affected individuals when it is in trans with another variant, homozygotes appear to be unaffected (PMID: 29771303). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2023	Variant summary: PAH c.355C>T (p.Pro119Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00029 in 251358 control chromosomes, predominantly at a frequency of 0.0023 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00029 vs 0.0079), allowing no conclusion about variant significance. c.355C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) or Hyperphenylalaninemia (e.g. Lindner_2003, Dobrowolski_2011, Esfahani_2018, Kuznetcova_2019, Su_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=2, likely pathogenic n=5, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The observed missense c.355C>T(p.Pro119Ser) variant in PAH gene has been reported previously in homozygous and compound heterozygous states in individuals affected with Phenylketonuria/Hyperphenylalaninemia (Kuznetcova I, et al., 2019; Su Y, et al., 2019; Esfahani MS & Vallian S., 2019). The p.Pro119Ser variant has been reported with allele frequency of 0.03% in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic / Likely Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on PAH gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 119 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic. In absence of another reportable variant in PAH gene, the molecular diagnosis is not confirmed -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 24, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 20, 2023	This variant is associated with phenylketonuria and hyperphenylalaninemia (PMIDs: 17924342 (2007), 21147011 (20111), and 35405047 (2022)). The variant has been reported as homozygous (PMID: 36537053 (2022)) or compound heterozygous with other pathogenic PAH variants in multiple individuals with PAH-related conditions (PMIDs: 31355225 (2019), 30389586 (2019), and 32668217 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2022	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: 15171997, 12655554, 34426522, 30389586, 32778825, 29771303, 21147011, 31355225) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2023

The c.355C>T (p.P119S) alteration is located in exon 4 (coding exon 4) of the PAH gene. This alteration results from a C to T substitution at nucleotide position 355, causing the proline (P) at amino acid position 119 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.029% (72/251358) total alleles studied. The highest observed frequency was 0.229% (70/30616) of South Asian alleles. This alteration has been reported compound heterozygous with a second alteration in PAH in multiple patients with biochemically confirmed PKU or hyperphenylalaninemia (Lindner, 2003; Esfahani, 2019; Su, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;T;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.37

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

M;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.7

D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.018

D;D;D

Sift4G

Uncertain

0.026

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.91

MVP

0.99

MPC

0.23

ClinPred

0.62

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.89

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