rs62642926

chr12-102912842-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000277.3(PAH):c.117C>G(p.Phe39Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000238 in 1,613,626 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 Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:19 O:1
• Conservation: PhyloP100: 3.73

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000277.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant 12-102912842-G-C is Pathogenic according to our data. Variant chr12-102912842-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 605.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102912842-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.117C>G	p.Phe39Leu	missense_variant	2/13	ENST00000553106.6
PAH	NM_001354304.2	c.117C>G	p.Phe39Leu	missense_variant	3/14
PAH	XM_017019370.2	c.117C>G	p.Phe39Leu	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.117C>G	p.Phe39Leu	missense_variant	2/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152182 Hom.: 0 Cov.: 33

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: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000955 AC: 24 AN: 251412 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135876

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000253 AC: 370 AN: 1461444 Hom.: 0 Cov.: 30 AF XY: 0.000250 AC XY: 182 AN XY: 727034

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000275 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the PAH protein (p.Phe39Leu). This variant is present in population databases (rs62642926, gnomAD 0.02%). This missense change has been observed in individual(s) with phenylketonuria, mild phenylketonuria and hyperphenylalaninemia (PMID: 2063869, 8592329, 8659548, 12655544, 12655553, 17935162). It is commonly reported in individuals of Scotland and Northern Ireland ancestry (PMID: 2063869, 8592329, 8659548, 12655544, 12655553, 17935162). ClinVar contains an entry for this variant (Variation ID: 605). 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 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: 1146119, 15557004, 17935162, 21953985, 25563416). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000277.1(PAH):c.117C>G(F39L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 8592329, 21953985, 10429004, 24368688, 26666653, and 12173030. Classification of NM_000277.1(PAH):c.117C>G(F39L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Mar 27, 2020	The c.117C>G (p.Phe39Leu) variant in PAH has been reported in multiple individuals with PKU. (PMID: 23430918, 8659548, 8406445, 2063869). This variant has an extremely low allele frequency in ExAC, gnomAD, 1000 Genomes, ESP (MAF=0.00016). This variant was detected with multiple pathogenic variants: T81P, V177L (PMID: 8659548), F55fsdelT (2 patients, PMID: 15557004), p.I65T, p.R408W (4 patients), p.R252W, p.E280K, c.1066-11G>A, c.1315+1G>A (PMID: 23430918). There is cosegregation with disease in affected siblings in 2 families PMID: 2063869, 8592329). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The PAH c.117C>G (p.F39L) missense variant has been reported in individuals with affected with phenylketonuria (PKU), mild PKU and hyperphenylalaninemia (PMID: 8592329; 8533759; 8659548; 12655553; 15557004). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 16, 2017	Variant summary: The PAH c.117C>G (p.Phe39Leu) variant located in the ACT domain (via InterPro) involves the alteration of a conserved nucleotide, which 3/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 11/121396 (1/11037), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals. Publications have indicated that the variant causes a mild-moderate phenotype. 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	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PAH c.117C>G (p.Phe39Leu) missense variant is well-described in the literature and has been identified individuals with varying phenotypes, ranging from classic phenylketonuria (PKU) to untreated hyperphenylalaninemia with normal intelligence (Forrest et al. 1991; Tyfield et al. 1995; Kayaalp 1997). Across a selection of the available literature the p.Phe39Leu variant has been reported in a compound heterozygous state in at least seven patients and in at least 101 of 1738 patient alleles where zygosity was not specified (Forrest et al. 1991; Guldberg et al. 1993; Tyfield et al. 1995; Zschocke et al. 1995; O'Donnell et al. 2002; Erlandsen et al. 2004; Zurflüh et al 2008; Polak et al. 2013). The p.Phe39Leu variant is more common in Scottish and Northern Irish PKU populations, with a frequency of approximately 6% and 9.5% respectively (Tyfield et al., 1995; Zschocke et al., 1995). In vitro functional analysis by Waters et al. (1999 and 2000) revealed that the variant is associated with increased protein aggregation and accelerated proteolytic degradation compared to wild type, as well as partial conversion of normal oligomeric protein forms to higher molecular weight aggregates. The p.Phe39Leu variant was absent from at least 236 controls and is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant is generally described as a BH4-responsive variant (Erlandsen et al. 2004; Zurflüh et al. 2008; Heintz et al. 2012). Based on the collective evidence, the p.Phe39Leu 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. -

not provided Pathogenic:5 Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Tetrahydrobiopterin (BH4) responsiveness is inconsistent in individuals who harbor the F39L variant (Zurfluh et al., 2008; Ho et al., 2014; Jeannesson-Thivisol et al., 2015; Aldmiz-Echevarra et al., 2016); This variant is associated with the following publications: (PMID: 11461190, 21953985, 27121329, 27760515, 8659548, 12655544, 23559577, 2063869, 25087612, 16338627, 29102225, 10429004, 8592329, 23430918, 25563416, 1146119, 12655553, 30037505, 15557004, 26666653, 24368688, 29030855, 30648773, 32853555, 32668217, 32778825, 33465300, 17935162, 27535533) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	PAH: PM3:Very Strong, PM2, PP4:Moderate, PP1 -

PAH-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2024

The PAH c.117C>G variant is predicted to result in the amino acid substitution p.Phe39Leu. This variant is documented as causative for phenylalanine hydroxylase deficiency, when found in the homozygous or compound heterozygous state (e.g., Guldberg et al. 1996. PubMed ID: 8659548; Sarkissian et al. 2012. PubMed ID: 23430918; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). In functional studies, the p.Phe39Leu amino acid change has been reported to result in reduced PAH protein levels as well as reduced enzyme activity (Zurflüh et al. 2008. PubMed ID: 17935162; Shi et al. 2012. PubMed ID: 21953985). Data regarding the responsiveness of patients with the p.Phe39Leu amino acid substitution to tetrahydrobiopterin (BH4) is conflicting (Zurflüh et al. 2008. PubMed ID: 17935162; Sarkissian et al. 2012. PubMed ID: 23430918). This variant is reported in 0.016% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It has been interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as numerous outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/605). This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2023

The c.117C>G (p.F39L) alteration is located in exon 2 (coding exon 2) of the PAH gene. This alteration results from a C to G substitution at nucleotide position 117, causing the phenylalanine (F) at amino acid position 39 to be replaced by a leucine (L). Based on data from gnomAD, the G allele has an overall frequency of 0.009% (26/282820) total alleles studied. The highest observed frequency was 0.016% (21/129140) of European (non-Finnish) alleles. This variant has been reported homozygous or with a second variant in PAH in multiple individuals diagnosed with phenylalanine hydroxylase deficiency (Forrest, 1991; Tyfield, 1995; Koch, 2005; Ho, 2014; Bayat, 2016; Ferreira, 2021). 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	0.96
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.5	D;D;D;D
REVEL	Pathogenic	0.75
Sift	Benign	0.10	T;T;D;D
Sift4G	Benign	0.18	T;T;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.94
MutPred		0.87		Loss of catalytic residue at F39 (P = 0.0777);.;Loss of catalytic residue at F39 (P = 0.0777);Loss of catalytic residue at F39 (P = 0.0777);
MVP		0.98
MPC		0.25
ClinPred		0.87	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.81

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

Other links and lift over

dbSNP: rs62642926; hg19: chr12-103306620;