12-102840399-C-T

Position:

chr12-102840399-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM3PP4_ModeratePVS1PS3

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PS3: abolishes PAH activity due to protein instability (PMID:17935162; PMID:3615198); PM3: (PMID:24941924); PP4_Moderate: Reported in Galician PAH deficiency population. BH4 deficiency ruled out. (PMID:23500595); PVS1: Canonical +1 splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM3, PP4_Moderate, PVS1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251522/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

PAH
NM_000277.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:31O:2

Conservation

PhyloP100: 7.46

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.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.1315+1G>A		splice_donor_variant, intron_variant		ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.1315+1G>A		splice_donor_variant, intron_variant			NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1315+1G>A		splice_donor_variant, intron_variant		1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000808

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000398

AC:

100

AN:

251412

Hom.:

AF XY:

0.000412

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

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:

0.000826

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00100

AC:

1449

AN:

1441894

Hom.:

Cov.:

AF XY:

0.000934

AC XY:

671

AN XY:

718700

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00129

Gnomad4 OTH exome

AF:

0.000435

GnomAD4 genome

AF:

0.000375

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000808

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.000514

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.000771

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:31Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:19Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 07, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change affects a donor splice site in intron 12 of the PAH gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs5030861, gnomAD 0.08%). Disruption of this splice site has been observed in individual(s) with PAH-related conditions (PMID: 24368688, 25596310, 26542770). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of European ancestry (PMID: 9634518, 24368688, 25596310, 26542770; Invitae). ClinVar contains an entry for this variant (Variation ID: 576). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects PAH function (PMID: 3615198, 17935162). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	Across a selection of the available literature, the PAH c.1315+1G>A variant, which occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product, is noted as one of the prevalent variants in the PAH gene. This variant has been identified in a homozygous state in at least 22 individuals with phenylalanine hydroxylase deficiency, in a compound heterozygous state in 151 patients, and in a heterozygous state in two patients (Guldberg et al. 1998; Koch et al. 2002; Bell et al. 2011; Bayat et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00105 in the European American population of the Exome Sequencing Project. The c.1315+1G>A variant was shown to cause skipping of exon 11, leading to loss of protein function (Marvit et al. 1987; Heintz et al. 2013; Couce et al. 2013). Based on the evidence from the literature and the potential impact of splice donor variants, the c.1315+1G>A 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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 3615198, 17935162, PS3_S). The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000000576, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000396, PM2_M). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 24941924, PM3_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Aug 10, 2018	- -
Pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The PAH c.1315+1G>A (p.?) variant is predicted to disrupt a canonical donor splice site. This variant is considered a severe PAH variant that has been observed in autosomal recessive classic phenylketonuria and is not responsive to tetrahydrobiopterin therapy. This variant has also been referred to in the literature as IVS12+1G>A (PMID: 3615198; 23500595; 12655544; 24190797; 17935162). -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Feb 04, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 08, 2022	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 05, 2018	PAH-specific ACMG/AMP criteria applied: PS3: abolishes PAH activity due to protein instability (PMID:17935162; PMID:3615198); PM3: (PMID:24941924); PP4_Moderate: Reported in Galician PAH deficiency population. BH4 deficiency ruled out. (PMID:23500595); PVS1: Canonical +1 splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM3, PP4_Moderate, PVS1). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 01, 2016	The c.1315+1G>A variant in PAH is a well-established variant in patients with classic PKU (Okano 1991, Zurfluh 2008). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein and in vitro functional studies provide evidence that the c.1315+1G>A variant impacts protein function (Okano 1991, Couce 2013, Heintz 2013, Zurfluh 2008, ). This variant has been identified in 0.06% (40/66664) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs5030861). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000277.1(PAH):c.1315+1G>A is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. The c.1315+1G>A variant is associated with classic PKU. Sources cited for classification include the following: PMID 22526846, 17502162, 9634518, 2014036 and 17935162. Classification of NM_000277.1(PAH):c.1315+1G>A 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, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2016	Variant summary: The c.1315+1G>A variant affects a conserved intronic nucleotide. One in-silico tool predicts damaging outcome for this variant and 5/5 splice-tools in Alamut predict that this variant abolishes a splice donor site at intron 12. This variant is found in 42/121228 control chromosomes at a frequency of 0.0003465, which does not exceed maximal expected frequency of a pathogenic allele (0.0079057). The variant has been reported in numerous affected individuals in the literature, is considered a common pathogenic variant in European populations, and has been shown to results in the complete absence of PAH activity. In addition, multiple reputable clinical labs have classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 24, 1987	- -

not provided

Pathogenic:9Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2020	Published functional studies demonstrate c.1315+1 G>A results in deletion of exon 12 and abolishes phenylalanine hydroxylase activity due to protein instability (Marvit et al., 1987); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al., 2008; Vela-Amieva et al., 2015); This variant is associated with the following publications: (PMID: 3008810, 23559577, 3018584, 22975760, 11914042, 26666653, 8406445, 24368688, 17935162, 25525159, 21228398, 3615198, 25087612, 24941924, 12655553, 11999982, 2014036, 26542770, 23500595, 24190797, 22526846, 30963030, 31589614, 33101986, 8188310, 32853555, 1677425) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 22, 2024	PP4_moderate, PM3, PS3, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 26, 2019	The PAH c.1315+1G>A pathogenic variant (also known as IVS12+1G>A) is located in a splice-donor site and interferes with normal PAH mRNA splicing. The variant has been identified in multiple individuals affected with PKU (PMID: 23500595 (2013), 25596310 (2015)). Functional studies indicate that this variant results in skipping of exon 12 in mRNA derived from patient cells and it has null to very low PAH activity (PMID: 3615198 (1987), 17935162 (2008)). -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PAH: PM3:Very Strong, PVS1, PM2, PP4:Moderate, PS3:Moderate -

PAH-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 12, 2023

The PAH c.1315+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, often referred to in the literature as IVS12+1G>A, disrupts the consensus splice donor site that lies at the junction of exon 12 and intron 12 and is predicted to adversely affect normal gene splicing (Alamut Visual v2.11). This variant has been reported to be causative for phenylalanine hydroxylase deficiency (e.g., Dobrowolski et al. 2009. PubMed ID: 19444284; Couce et al. 2013. PubMed ID: 23500595; Vela-Amieva et al. 2015. PubMed ID: 24941924; Sarkissian et al. 2012. PubMed ID: 23430918). The c.1315+1G>A variant has been reported to completely abrogate phenylalanine hydroxylase enzyme activity and has been associated with classic phenylketonuria (PKU) (Zurflüh et al. 2008. PubMed ID: 17935162; Couce et al. 2013. PubMed ID: 23500595). Additionally, it has been reported to result in a PAH protein that is non-responsive to BH4 (Zurflüh et al. 2008. PubMed ID: 17935162). This variant is classified as pathogenic by multiple outside laboratories and the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/576/). Based on these observations, we interpret this variant as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2021

The c.1315+1G>A intronic alteration consists of a G to A substitution one nucleotide after coding exon 12 of the PAH gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the PAH c.1315+1G>A alteration was observed in 0.04% (112/282,806) of total alleles studied, with a frequency of 0.08% (105/129,170) in the European (non-Finnish) subpopulation. The c.1315+1G>A alteration has been observed in both the homozygous state and compound heterozygous state in multiple unrelated individuals (Dihella 1986; Tabor, 2014; Xiong, 2015). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Pituitary hormone deficiency, combined, 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 21, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.94

Position offset: 1

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

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