12-102866599-C-T

Variant names:

• chr12-102866599-C-T
• rs199475679
• NM_000277.3:c.506G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PP4_Moderate: This variant has been reported in multiple mild hyperphenylalaninaemia (MHP) patients, with BH4 defects excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:10234516); PM3_Strong: Detected with P281L and A403V, both pathogenic variants (PMID:10234516). 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: (PP4_Moderate, PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA286505/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:20 U:3 O:1
• Conservation: PhyloP100: 2.06
• Publications: 18 publications found

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

LOC124902999 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM3: 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 rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.506G>A	p.Arg169His	missense_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.506G>A	p.Arg169His	missense_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2	c.506G>A	p.Arg169His	missense_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1	n.807+1372C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.506G>A	p.Arg169His	missense_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5	n.602G>A		non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7	c.491G>A	p.Arg164His	missense_variant	Exon 6 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5	n.530+10863G>A		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152092 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000299 AC: 75 AN: 250586 AF XY: 0.000251

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00597

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000201 AC: 293 AN: 1460206 Hom.: 0 Cov.: 30 AF XY: 0.000198 AC XY: 144 AN XY: 726554

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00498 AC: 130 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.000111 AC: 123 AN: 1110540

Other (OTH) AF: 0.000514 AC: 31 AN: 60332

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152092 Hom.: 1 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.000197 AC: 3 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68014

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000363 Hom.: 2

Bravo AF: 0.000178

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:20 Uncertain:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:15

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 11, 2019

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PAH-specific ACMG/AMP criteria applied: PP4_Moderate: This variant has been reported in multiple mild hyperphenylalaninaemia (MHP) patients, with BH4 defects excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:10234516); PM3_Strong: Detected with P281L and A403V, both pathogenic variants (PMID:10234516). 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: (PP4_Moderate, PM3_Strong). -

Jan 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 07, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 18, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg169His variant in PAH has been reported in 18 individuals with phenylalanine hydroxylase deficiency including 16 compound heterozygotes and one homozygote (Desviat 1999 PMID: 10234516, Wang 2018 PMID: 29499199, Su 2019 PMID: 31355225, Hillert 2020 PMID: 32668217), many of whom presented with classical phenylketo It has also been identified 0.55% (19/3472) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar as likely pathogenic by the ClinGen PAH Variant Curation Expert Panel using the . ACMG-AMP criteria specific for phenylalanine hydroxylase variants (Zastrow 2018 PMID: 30311390) and is curated in the FDA-recognized human genetic variant database (Variation ID 102706). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Three additional variants involving this codon (p.Arg169Ser, p.Arg169Gly, and p.Arg169Cys) have been identified in individuals with phenylalanine hydroxylase deficiency and are classified as likely pathogenic or pathogenic by the ClinGen PAH Variant Curation Expert Panel. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylalanine hydroxylase deficiency. ACMG/AMP Criteria applied: PP4_Moderate, PM5, BS1_Supporting, PM3_VeryStrong. -

Nov 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 12, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant, NM_000277.1(PAH):c.506G>A, has been identified in exon 5 of 13 of the PAH gene. The variant is predicted to result in a minor amino acid change from an arginine to a histidine at position 169 of the protein, NP_000268.1(PAH):p.(Arg169His). The arginine residue at this position has moderate conservation (100 vertebrates, UCSC), and is located within the Biopterin domain. In silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.029% (78 heterozygotes, 1 homozygote). The variant has previously been described as pathogenic or VUS in multiple patients with mild phenylalanine hydroxylase deficiency (ClinVar). Different variants in the same codon resulting in a change to proline and cysteine, p.(Arg169Pro) and p.(Arg169Cys) have been reported in patients with phenylketonuria (ClinVar). Analysis of parental samples indicated this variant was paternally inherited and to be present in cis with the second reported PAH variant. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. <br /> -

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 169 of the PAH protein (p.Arg169His). This variant is present in population databases (rs199475679, gnomAD 0.7%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 10234516, 18299955, 21147011, 26666653, 28982351). ClinVar contains an entry for this variant (Variation ID: 102706). 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%. This variant disrupts the p.Arg169 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26503515, 29499199, 30050108). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 04, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PAH c.506G>A (p.Arg169His) missense variant has been reported in five studies in which it is found in a total of six patients with phenylalanine hydroxylase (PAH) deficiency including in two in a compound heterozygous state with another missense variant, two in heterozygous state with a mild form of phenylalanine hydroxylase deficiency, and two with unknown zygosity (Desviat et al. 1999; Aulehla-Scholz et al. 2003; Bercovich et al. 2008a; Bercovich et al. 2008b; Réblová et al. 2013). The p.Arg169His variant was absent from at least 200 controls and is reported at a frequency of 0.00046 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg169His variant is classified as likely pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Mar 23, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2 Uncertain:3 Other:1

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 15, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 29789446, 29316886, 23357515, 26982749, 21147011, 12655553, 18294361, 11385716, 19015950, 33677757, 30311390, 29499199, 31355225, 34426522, 33101986, 18299955, 17924342, 31980526, 32668217, 26666653, 10234516, 35405047, 35355500, 34405919, 28982351, 31623983, 30050108, 26582918, 29997390, 35281663, 38706300, 38731816, 31947737, 37837865, 38532509) -

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Feb 01, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.506G>A (p.R169H) alteration is located in exon 5 (coding exon 5) of the PAH gene. This alteration results from a G to A substitution at nucleotide position 506, causing the arginine (R) at amino acid position 169 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of 0.03% (77/281982) total alleles studied. The highest observed frequency was 0.59% (61/10348) of Ashkenazi Jewish alleles. This alteration has been reported in the compound heterozygous state with a second PAH alteration in multiple patients with hyperphenylalaninemia (Desviat, 1999; Dobrowolski, 2011; Jeannesson-Thivisol, 2015; Liu, 2017; Rajabi, 2019). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, R169H is deleterious. The variant is mildly destabilizing to the local structure. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Pulmonary hypertension, primary, 1 Pathogenic:1

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:1

Jun 28, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.506G>A (p.Arg169His) results in a non-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 0.00026 in 395274 control chromosomes in the gnomAD database (v2.1 and v3.1 datasets), including 1 homozygote. This frequency is not higher than the maximum expected for a pathogenic variant in PAH causing Hyperphenylalaninemia (0.00026 vs 0.0079), allowing no conclusion about variant significance. c.506G>A, has been reported in the literature in multiple mild hyperphenylalaninaemia (MHP) patients with another pathogenic variant on the other allele (e.g. Desviat_1999, Bercovich_2008, Jeannesson-Thivisol_2015, Liu_2017, Garbade_2019, Rajabi_2019, Ngiwsara_2021). In addition, a recent meta-analysis reported the variant in several compound heterozygous patients and in one homozygote, in association with MHP, and an allelic phenotype value of 10 (Hillert_2020). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant had a residual activity of 52% of the wild type enzyme (Ngiwsara_2021). Nine other submitters, including one expert panel (ClinGen), have provided clinical-significance assessments for this variant in ClinVar after 2014 and classified the variant as likely pathogenic (n=6; including the expert panel), pathogenic (n=1) and VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;.
PhyloP100		2.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.74	P;.
Vest4		0.79
MutPred		0.91		Loss of MoRF binding (P = 0.0185);.;
MVP		0.96
MPC		0.037
ClinPred		0.22	T
GERP RS		5.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.37
gMVP		0.87
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs199475679; hg19: chr12-103260377; COSMIC: COSV61016255;