chr12-102894826-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong

The NM_000277.3(PAH):c.261C>A(p.Ser87Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,613,804 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S87S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 0.967

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000277.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 440 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: -0.64755 (below the threshold of 3.09). Trascript score misZ: -0.0084567 (below the threshold of 3.09). GenCC associations: The gene is linked to phenylketonuria, tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria, maternal phenylketonuria, classic phenylketonuria, mild phenylketonuria, mild hyperphenylalaninemia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 12-102894826-G-T is Pathogenic according to our data. Variant chr12-102894826-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.261C>A	p.Ser87Arg	missense_variant	Exon 3 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.261C>A	p.Ser87Arg	missense_variant	Exon 4 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.261C>A	p.Ser87Arg	missense_variant	Exon 3 of 7		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.863-9872G>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.261C>A	p.Ser87Arg	missense_variant	Exon 3 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152112

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000756

AC:

AN:

251450

AF XY:

0.0000957

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000123

AC:

180

AN:

1461574

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.000201

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000149

AC:

166

AN:

1111742

Other (OTH)

AF:

0.0000497

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000831

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 87 of the PAH protein (p.Ser87Arg). This variant is present in population databases (rs62516151, gnomAD 0.01%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 8088845, 10495930). ClinVar contains an entry for this variant (Variation ID: 583). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 23500595). For these reasons, this variant has been classified as Pathogenic. -

Mar 25, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 14, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PAH c.261C>A (p.Ser87Arg) missense variant has been reported in a compound heterozygous state in six unrelated individuals with phenylalanine hydroxylase deficiency, including in five with mild hyperphenylalaninemia and in one with mild phenylketonuria (Guldberg et al. 1994; Zekanowski et al. 1999; Desviat et al. 2004; Bueno et al. 2013; Ohlsson et al. 2017). The p.Ser87Arg variant was also identified in at least one additional individual, but the zygosity of the variant was not provided (ZurflÃ¼h et al. 2008; Couce et al. 2013). The variant was absent from 220 control chromosomes, but is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. In addition, Couce et al. (2013) report data from the PAHdb which indicates in vitro residual PAH activity at 25-82% of wild type for the variant. Based on the evidence, the p.Ser87Arg variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Dec 24, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2Other:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hyperphenylalaninemia

Pathogenic:2

Aug 07, 2017

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PAH c.261C>A (p.Ser87Arg) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools (MutationTaster not captured here due to low p-value) predict a damaging outcome. This variant was found in 10/121410 control chromosomes at a frequency of 0.0000824, 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 affected individuals via publication, predominantly showing a mild HPA phenotype. In addition, a clinical diagnostic laboratory and reputable database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

May 15, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PAH-related disorder

Pathogenic:1

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PAH c.261C>A variant is predicted to result in the amino acid substitution p.Ser87Arg. This variant has been reported along with a second causative PAH variant in multiple patients with phenylalanine hydroxylase deficiency (Guldberg et al. 1994. PubMed ID: 8088845; Zekanowski et al. 1999. PubMed ID: 10495930; Desviat et al. 2004. PubMed ID: 15464430; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Table S3, Hillert A et al 2020. PubMed ID: 32668217). This variant has been reported to be associated with mild hyperphenylalaninemia (Table S2, Hillert A et al 2020. PubMed ID: 32668217). Internally, we have observed this variant along with a second causative PAH variant in patients with abnormal newborn screen results suggestive of phenylalanine hydroxylase deficiency. The p.Ser87 amino acid resides in the PAH regulatory domain, and in functional studies the p.Ser87Arg substitution has been reported to reduce activity of the PAH enzyme to between ~25-82% of wild-type (Gjetting et al. 2001. PubMed ID: 11161839; Couce et al. 2013. PubMed ID: 23500595). The p.Ser87Arg substitution has been reported to result in a PAH enzyme that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). A different nucleotide change leading to the same amino acid substitution (c.259A>C, p.Ser87Arg) has also been reported in association with phenylalanine hydroxylase deficiency (Himmelreich et al. 2018. PubMed ID: 30037505). The c.261C>A (p.Ser87Arg) variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Based on these observations, this variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jan 26, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.261C>A (p.S87R) alteration is located in coding exon 3 of the PAH gene. This alteration results from a C to A substitution at nucleotide position 261, causing the serine (S) at amino acid position 87 to be replaced by an arginine (R). Based on data from the Genome Aggregation Database (gnomAD), the PAH c.261C>A alteration was not observed, with coverage at this position. The c.261C>A (p.S87R) alteration has been reported in combination with a second pathogenic alteration in multiple unrelated families presenting with hyperphenylalaninemia and mild PKU (Bueno, 2013; Desviat, 2004; Guldberg, 1993; Jeannesson-Thivisol, 2015; Rajabi, 2019). The p.S87 amino acid is not conserved in available vertebrate species. The in silico prediction for the p.S87R alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.71

D;T;T;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.72

T;T;T;T

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.2

L;.;.;.

PhyloP100

0.97

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Uncertain

0.63

Sift

Benign

0.51

T;T;T;T

Sift4G

Benign

0.51

T;T;T;.

Polyphen

0.091

B;.;.;.

Vest4

0.90

MutPred

0.79

Gain of MoRF binding (P = 0.0584);.;Gain of MoRF binding (P = 0.0584);Gain of MoRF binding (P = 0.0584);

MVP

0.86

MPC

0.046

ClinPred

0.051

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.82

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over