12-102866641-C-T

Position:

chr12-102866641-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP1PP3PM2PP4_ModeratePM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.464G>A (p.Arg155His) has been reported in multiple individuals with mild hyperphenylalaninaemia, with BH4 deficiency excluded including 3 siblings (PP4_moderate, PMID:9634518; PP1, PMID:18937047). This variant has low frequency in ExAC/gnomad (MAF=0.00012) in EA population (PM2). Multiple lines of computational evidence support a deleterious effect (PP3). This variant has been detected with 3 pathogenic variants: R243Q (PMID:23932990), R111X (PMID:24401910), IVS4+5G>T c.441+5G>T (PMID:26210745) (PM3-strong). Experimental study showed the R155H mutant retained 55% activity, but this is higher than the cutoff set by PAH VCEP for PS3. (PMID:18937047). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PP3, PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229559/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

14

4

1

Clinical Significance

Pathogenic reviewed by expert panel P:10O:1

Conservation

PhyloP100: 5.24

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 10 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.

PP1

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.464G>A	p.Arg155His	missense_variant	5/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.464G>A	p.Arg155His	missense_variant	6/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.464G>A	p.Arg155His	missense_variant	5/7		XP_016874859.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.807+1414C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.464G>A	p.Arg155His	missense_variant	5/13	1	NM_000277.3	ENSP00000448059.1		P00439
PAH	ENST00000549111.5 linkuse as main transcript	n.560G>A		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.449G>A	p.Arg150His	missense_variant	6/14	5		ENSP00000303500.2		J3KND8
PAH	ENST00000551988.5 linkuse as main transcript	n.530+10821G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152132

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

5

AN:

251348

Hom.:

0

AF XY:

0.0000147

AC XY:

2

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

42

AN:

1461372

Hom.:

0

Cov.:

31

AF XY:

0.0000261

AC XY:

19

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000263

AC:

4

AN:

152132

Hom.:

0

Cov.:

32

AF XY:

0.0000538

AC XY:

4

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

0

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

3

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2019	Variant summary: PAH c.464G>A (p.Arg155His) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251348 control chromosomes. c.464G>A has been reported in the literature in multiple individuals affected with Hyperphenylalaninemia (Guldberg_1998, Dobrowolski_2009) and Phenylketonuria (Trunzo_2015, Baturina_2016). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (Dobrowolski_2009, Himmelreich_2018) . The most pronounced variant effect results in 10%-<30% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Apr 07, 2019	The c.464G>A (p.Arg155His) has been reported in multiple individuals with mild hyperphenylalaninaemia, with BH4 deficiency excluded including 3 siblings (PP4_moderate, PMID: 9634518; PP1, PMID:18937047). This variant has low frequency in ExAC/gnomad (MAF=0.00012) in EA population (PM2). Multiple lines of computational evidence support a deleterious effect (PP3). This variant has been detected with 3 pathogenic variants: R243Q (PMID: 23932990), R111X (PMID: 24401910), IVS4+5G>T c.441+5G>T (PMID: 26210745) (PM3-strong). Experimental study showed the R155H mutant retained 55% activity, but this is higher than the cutoff set by PAH VCEP for PS3. (PMID: 18937047). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_strong, PM2, PP3, PP1. -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 155 of the PAH protein (p.Arg155His). This variant is present in population databases (rs199475663, gnomAD 0.01%). This missense change has been observed in individual(s) with hyperphenylalaninaemia and/or phenylketonuria (PMID: 18937047, 23932990, 24401910, 26210745, 28754886). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 102686). 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: 18937047). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 26, 2022	The p.Arg155His variant in PAH has been reported in at least 19 individuals with phenylalanine hydroxylase deficiency/phenylketonuria (PKU)/hyperphenylalaninemia (HPA) (Trunzo 2015 PMID: 26210745, Liang 2014 PMID: 24401910, Zhu 2013 PMID: 23932990, Guldberg 1998 PMID: 9634518, and Cinar 2022 PMID: 35355500), including 4 siblings in one family and members of 5 additional families (Dabrowolski SF 2011 PMID: 21147011, Dabrowolski 2009 PMID: 18937047). All of these individuals were compound heterozygous for a second pathogenic PAH variant. It has been identified in 0.0003% of ASJ chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as pathogenic on 01/20/20 by the ClinGen PAH Variant Curation Expert Panel (Variation ID: 102686). Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to to determine pathogenecity. In vitro functional studies support an impact of p.Arg155His on protein function, although the degree of impact is debated (21% and 55% reduced activity as compared to wildtype, respectively) (Himmelreich 2018 PMID: 30037505, Dabrowolski 2008 PMID: 18937047). This variant occurs in exon 5 of PAH where numerous pathogenic variants in PAH have been identified, including at the same residue (p.Arg155Cys, p.Arg155Pro). In summary, c.464G>A (p.Arg155His) meets criteria to be classified as pathogenic for autosomal recessive PAH deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PM5_Strong, PM2_Supporting, PP3, PP4, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	-	PM2+PM3_VS+PP3+PP4_M -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Pathogenic:1Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2020	R155H classified as variant associated with mild hyperphenylalaninemia (Guldberg et al., 1998), however it has been reported in patients with mild and classic PKU (Dobrowolski et al., 2011; Zhu et al., 2013); In vitro functional studies of p.R155H demonstrate a mild functional effect and is associated with mild HPA (Himmelreich et al., 2018; Dobrowolski et al., 2009); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Responsiveness to BH4 is unknown (Trunzo et al., 2015); This variant is associated with the following publications: (PMID: 32668217, 30275481, 31980526, 30747360, 26210745, 21147011, 23932990, 29499199, 30037505, 27264808, 18937047, 9634518, 24401910, 28754886) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.44

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

29

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.81

D

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

4.4

H;.

PrimateAI

Uncertain

0.68

T

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.85

MVP

0.99

MPC

0.26

ClinPred

1.0

D

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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: rs199475663; hg19: chr12-103260419; COSMIC: COSV61016854;