12-102852929-C-T

Position:

chr12-102852929-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000277.3(PAH):c.728G>A(p.Arg243Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R243L) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19O: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 16 ACMG points.

PM1

In a strand (size 3) in uniprot entity PH4H_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000277.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-102852929-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

PP5

Variant 12-102852929-C-T is Pathogenic according to our data. Variant chr12-102852929-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-102852929-C-T is described in Lovd as [Pathogenic]. Variant chr12-102852929-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.728G>A	p.Arg243Gln	missense_variant	7/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.728G>A	p.Arg243Gln	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.728G>A	p.Arg243Gln	missense_variant	7/13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000307000.7 linkuse as main transcript	c.713G>A	p.Arg238Gln	missense_variant	8/14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000549247.6 linkuse as main transcript	n.487G>A		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152042

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:

0.000193

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

251112

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000451

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000353

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000574

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.728G>A;p.(Arg243Gln) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 591; PMID: 29499199; 28676969; 24401910; 14722928) - PS4. The variant is present at low allele frequencies population databases (rs62508588– gnomAD 0.0002631%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Arg243Gln) was detected in trans with a Pathogenic variant (PMID: 24401910; 14722928) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -
Pathogenic, no assertion criteria provided	case-control	Biochemistry Laboratory of CDMU, Chengde Medical University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 243 of the PAH protein (p.Arg243Gln). This variant is present in population databases (rs62508588, gnomAD 0.03%). This missense change has been observed in individual(s) with phenylketonuria (PKU) (PMID: 2071149, 23716935, 24401910, 24705691, 27264808). ClinVar contains an entry for this variant (Variation ID: 591). 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: 12655546, 21953985, 23500595). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 03, 2017	Variant summary: The PAH c.728G>A (p.Arg243Gln) variant located in the aromatic amino acid hydroxylase, C-terminal (InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 19/245876 control chromosomes at a frequency of 0.0000773, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). The variant of interest has been reported in multiple publications in affected compound heterozygote and homozygote individuals presenting with classic PKU, mild PKU, HPA, and mild-HPA. Activity levels for these affected individuals were indicated to have been significantly reduced in comparison to wild type (Aldamiz-Echevarria_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	Sep 19, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 22, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1992	- -
Pathogenic, no assertion criteria provided	clinical testing	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	-	PS3+PM3_VS+PP1_S+PP3+PP4_M -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PS3+PM3_VeryStrong+PP4 -

not provided

Pathogenic:4Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 31, 2018	The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2021	Reported to be associated with approximately 10-18% residual phenylalanine hydroxylase activity compared to wild-type (Shi et al., 2012; Couce et al., 2013; Liang et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported to be responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 28851938, 28676969, 17935162, 24401910, 2071149, 27264808, 25750018, 23500595, 21953985, 12655546, 29317692, 29499199, 11243094, 30037505, 29909188, 30648773, 31178897, 30678510, 31355225, 30747360, 31998365, 30275481, 34426522, 33677757, 31589614, 32778825, 33465300, 29288420, 33375644) -

PAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

The PAH c.728G>A variant is predicted to result in the amino acid substitution p.Arg243Gln. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with phenylketonuria (Couce et al. 2013. PubMed ID: 23500595; Table 2, Ghanei et al. 2023. PubMed ID: 36646061) and is one of the most common pathogenic PAH variants in the Chinese population (see for example, Lee et al. 2004. PubMed ID: 15503242; Song et al. 2005. PubMed ID: 16256386; Liang et al. 2014. PubMed ID: 24401910). This variant is reported in 0.038% of alleles in individuals of East Asian decent in gnomAD. In vitro experimental studies suggest this variant reduces enzyme activity to ~10-20% of control (Table 1, Shi et al. 2012. PubMed ID: 21953985; Couce et al. 2013. PubMed ID: 23500595; Liang et al. 2014. PubMed ID: 24401910). This variant is classified as pathogenic and likely pathogenic in ClinVar by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/591/). Taken together, we classify this variant as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

D;.

Vest4

0.95

MVP

0.98

MPC

0.25

ClinPred

0.94

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.95

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.

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