VCV000000576.135 - ClinVar

NM_000277.3(PAH):c.1315+1G>A

Germline

Top reviewed classifications are shown here.

Submission summary:

33 submissions

33 submitters

5 conditions

Reviewed by expert panel

Pathogenic

Aug 2018 by ClinGen PAH Va… FDA Recognized Database

for Phenylketonuria

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000277.3(PAH):c.1315+1G>A

Variation ID: 576 Accession: VCV000000576.135

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.2 12: 102840399 (GRCh38) [ NCBI UCSC ] 12: 103234177 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 19, 2014	Jan 19, 2025	Aug 5, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.1315+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001354304.2:c.1315+1G>A		splice donor
NC_000012.12:g.102840399C>T
NC_000012.11:g.103234177C>T
NG_008690.2:g.123012G>A

... more HGVS ... less HGVS

Protein change

Other names

NM_000277.2(PAH):c.1315+1G>A
IVS12+1G>A
IVS12DS, G-A, +1

Canonical SPDI

NC_000012.12:102840398:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00035

The Genome Aggregation Database (gnomAD) 0.00040

The Genome Aggregation Database (gnomAD), exomes 0.00040

Trans-Omics for Precision Medicine (TOPMed) 0.00051

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00077

Links

ClinGen: CA251522 OMIM: 612349.0001 dbSNP: rs5030861 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PAH		-	-	GRCh38 GRCh37	1525	1650

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Phenylketonuria	Pathogenic (20)	reviewed by expert panel	Aug 5, 2018	RCV000000606.107
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	May 1, 2024	RCV000078510.52
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 5, 2021	RCV000622610.9
PAH-related disorder	Pathogenic (1)	criteria provided, single submitter	Oct 12, 2023	RCV003407249.5
Pituitary hormone deficiency, combined, 2	Pathogenic (1)	criteria provided, single submitter	Jan 21, 2020	RCV004799176.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 05, 2018)	reviewed by expert panel (ClinGen PAH ACMG Specifications v1) Method: curation	Phenylketonuria (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen PAH Variant Curation Expert Panel FDA Recognized Database Accession: SCV000852099.4 First in ClinVar: May 26, 2018 Last updated: Dec 11, 2022	Publications: PubMed (4) PubMed: 23500595‚ 24941924‚ 3615198‚ 17935162 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a0e84b26-03d1-42c0-a937-859d45d287e0 Comment: 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 … (more) 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). (less)
Pathogenic (Oct 07, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Phenylketonuria Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000745568.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Pathogenic (May 03, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110366.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018	Publications: PubMed (3) PubMed: 11999982‚ 23500595‚ 3008810 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH http://www.pahdb.mcgill.ca/ http://www.pahdb.mcgill.ca/ Number of individuals with the variant: 71 Zygosity: Homozygote, Single Heterozygote Sex: mixed
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Phenylketonuria Affected status: yes Allele origin: germline	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: NSIGHT-NC NEXUS Accession: SCV001251467.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (6) PubMed: 20301677‚ 3615198‚ 23500595‚ 12655544‚ 24190797‚ 17935162 Comment: 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 … (more) 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). (less) Number of individuals with the variant: 3
Pathogenic (Aug 10, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448977.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Clinical Features: Intellectual disability (present) , Short stature (present) , Failure to thrive (present) , Behavioral abnormality (present) , Inguinal hernia (present) , Autistic disorder of childhood … (more) Intellectual disability (present) , Short stature (present) , Failure to thrive (present) , Behavioral abnormality (present) , Inguinal hernia (present) , Autistic disorder of childhood onset (present) , Gait disturbance (present) , Psychosis (present) , Exotropia (present) , Thrombocytopenia (present) , Hypothyroidism (present) , Expressive language delay (present) , Constipation (present) , Attention deficit hyperactivity disorder (present) , Status epilepticus (present) , Seizures (present) , Cerebral atrophy (present) , Bipolar affective disorder (present) , Migraine (present) , Receptive language delay (present) , Chronic obstructive airway disease from birth (present) , Global developmental delay (present) , Feeding difficulties (present) , Inappropriate behavior (present) (less) Sex: male
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: yes Allele origin: germline	3billion Accession: SCV002059116.1 First in ClinVar: Jan 14, 2022 Last updated: Jan 14, 2022	Publications: PMID:17935162 PMID:17935162 PMID:3615198 PMID:3615198 Comment: 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 … (more) 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. (less) Clinical Features: Delayed speech and language development (present) , Hypertonia (present) Zygosity: Single Heterozygote
Pathogenic (Jan 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761837.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009278.3 First in ClinVar: Nov 05, 2021 Last updated: Jul 16, 2023
Pathogenic (Oct 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PAH-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004106519.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Dec 28, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002016490.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000629184.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (8) PubMed: 24368688‚ 25596310‚ 26542770‚ 9634518‚ 3615198‚ 17935162‚ 17576681‚ 9536098 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847982.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (6) PubMed: 25525159‚ 17935162‚ 2014036‚ 23500595‚ 23559577‚ 3008810 Comment: 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 … (more) 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. (less)
pathogenic (Apr 02, 2024)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888344.4 First in ClinVar: Mar 13, 2019 Last updated: Jan 19, 2025	Publications: PubMed (20) PubMed: 3615198‚ 3008810‚ 21228398‚ 23500595‚ 23559577‚ 22975760‚ 2014036‚ 25087612‚ 25525159‚ 17935162‚ 9634518‚ 23430918‚ 25596310‚ 34828281‚ 33375644‚ 37189584‚ 36646061‚ 24941924‚ 24368688‚ 26542770 Comment: The PAH c.1315+1G>A variant disrupts a canonical splice-donor site and interferes with normal PAH mRNA splicing. This variant has been reported in homozygous or compound … (more) The PAH c.1315+1G>A variant disrupts a canonical splice-donor site and interferes with normal PAH mRNA splicing. This variant has been reported in homozygous or compound heterozygous states in multiple individuals with PKU (PMIDs: 9634518 (1998), 24368688 (2014), 24941924 (2015), 25596310 (2015), 26542770 (2016), 33375644 (2020), 34828281 (2021)). Experimental studies indicate that this variant results in skipping of exon 12 in mRNA derived from patient cells and it has to very low PAH activity due to protein instability (PMIDs: 3615198 (1987), 17935162 (2008)). The frequency of this variant in the general population, 0.001 (51/50816 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (May 06, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000696436.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (4) PubMed: 17935162‚ 24190797‚ 22526846‚ 24368688 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 08, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Phenylketonuria Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000744088.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Pathogenic (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914551.1 First in ClinVar: May 24, 2019 Last updated: May 24, 2019	Publications: PubMed (7) PubMed: 11914042‚ 3615198‚ 23500595‚ 9634518‚ 26542770‚ 23559577‚ 21228398 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 20, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194237.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (5) PubMed: 22526846‚ 17502162‚ 9634518‚ 2014036‚ 17935162 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 04, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367030.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Pathogenic (Mar 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611231.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 31, 2022
Pathogenic (Feb 25, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000239096.12 First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023	Comment: 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); … (more) 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) (less)
Pathogenic (Jan 05, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000742847.5 First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 3008810‚ 25087612‚ 25525159 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001163708.2 First in ClinVar: Mar 01, 2020 Last updated: Jun 17, 2024
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005197065.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jan 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414098.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Comment: PP4_moderate, PM3, PS3, PVS1 Number of individuals with the variant: 6
Pathogenic (Jan 21, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Pituitary hormone deficiency, combined, 2 Affected status: unknown Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001432828.2 First in ClinVar: Sep 27, 2020 Last updated: Dec 14, 2024	Clinical Features: Autism (present) , Syncope (present) , Seizure (present) Zygosity: Single Heterozygote Secondary finding: no
Pathogenic (May 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001247317.27 First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024	Comment: PAH: PM3:Very Strong, PVS1, PM2, PP4:Moderate, PS3:Moderate Number of individuals with the variant: 11
Pathogenic (Jul 24, 1987)	no assertion criteria provided Method: literature only	PHENYLKETONURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020756.67 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 3008810‚ 3615198 Comment on evidence: The first phenylketonuria (PKU; 261600) mutation identified in the PAH gene was a single base change (GT to AT) in the canonical 5-prime splice donor … (more) The first phenylketonuria (PKU; 261600) mutation identified in the PAH gene was a single base change (GT to AT) in the canonical 5-prime splice donor site of intron 12 (DiLella et al., 1986). Direct hybridization analysis using specific oligonucleotide probes demonstrated tight association with a specific RFLP haplotype called haplotype 3. The splicing mutation was the most prevalent PKU allele among Caucasians. Marvit et al. (1987) found that the GT-to-AT substitution at the 5-prime splice donor site of intron 12 resulted in the skipping of the preceding exon during RNA splicing. cDNA clones had shown an internal 116-basepair deletion corresponding precisely to exon 12 and leading to the synthesis of the truncated protein lacking the C-terminal 52 amino acids. Gene transfer and expression studies using the mutant PAH cDNA indicated that the deletion abolished PAH activity in the cell as a result of protein instability. The studies of Marvit et al. (1987) indicated that in fact a single nucleotide substitution rather than a deletion was the basis of the abnormal gene product. (less)
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458993.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Phenylketonuria Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733120.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809008.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001958569.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE Accession: SCV000119418.1 First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014
not provided (-)	no classification provided Method: literature only	Phenylketonuria Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000324892.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1504 BookShelf: NBK1504
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Comment:

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).

Comment:

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).

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

The PAH c.1315+1G>A variant disrupts a canonical splice-donor site and interferes with normal PAH mRNA splicing. This variant has been reported in homozygous or compound heterozygous states in multiple individuals with PKU (PMIDs: 9634518 (1998), 24368688 (2014), 24941924 (2015), 25596310 (2015), 26542770 (2016), 33375644 (2020), 34828281 (2021)). Experimental studies indicate that this variant results in skipping of exon 12 in mRNA derived from patient cells and it has to very low PAH activity due to protein instability (PMIDs: 3615198 (1987), 17935162 (2008)). The frequency of this variant in the general population, 0.001 (51/50816 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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)

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
PAH Pathogenic Variants and Clinical Correlations in a Group of Hyperphenylalaninemia Patients from North-Western Romania.	Iuhas A	Diagnostics (Basel, Switzerland)	2023	PMID: 37189584
A Comprehensive Study of Disease-Causing Variants in PAH, QDPR, PTS, and PCD Genes in Iranian Patients with Hyperphenylalaninemia: A Systematic Review.	Ghanei M	Human heredity	2023	PMID: 36646061
An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations.	Vela-Amieva M	Genes	2021	PMID: 34828281
Phenylketonuria Diagnosis by Massive Parallel Sequencing and Genotype-Phenotype Association in Brazilian Patients.	Tresbach RH	Genes	2020	PMID: 33375644
Phenylalanine Hydroxylase Deficiency.	Adam MP	-	2017	PMID: 20301677
Mutational and phenotypical spectrum of phenylalanine hydroxylase deficiency in Denmark.	Bayat A	Clinical genetics	2016	PMID: 26542770
Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria.	Danecka MK	Journal of medical genetics	2015	PMID: 25596310
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Phenylalanine hydroxylase deficiency in Mexico: genotype-phenotype correlations, BH4 responsiveness and evidence of a founder effect.	Vela-Amieva M	Clinical genetics	2015	PMID: 24941924
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.	Tabor HK	American journal of human genetics	2014	PMID: 25087612
The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness.	Ho G	JIMD reports	2014	PMID: 24368688
Influence of PAH Genotype on Sapropterin Response in PKU: Results of a Single-Center Cohort Study.	Leuders S	JIMD reports	2014	PMID: 24190797
Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase, and importance of genotypes for pharmacological therapy of phenylketonuria.	Heintz C	Human mutation	2013	PMID: 23559577
Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain.	Couce ML	Gene	2013	PMID: 23500595
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals.	Lazarin GA	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22975760
Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients.	Sterl E	Journal of inherited metabolic disease	2013	PMID: 22526846
Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response?	Sarkissian CN	JIMD reports	2012	PMID: 23430918
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.	Zurflüh MR	Human mutation	2008	PMID: 17935162
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Mutations in the phenylalanine hydroxylase gene identified in 95 patients with phenylketonuria using novel systems of mutation scanning and specific genotyping based upon thermal melt profiles.	Dobrowolski SF	Molecular genetics and metabolism	2007	PMID: 17502162
Phenylketonuria mutations in Europe.	Zschocke J	Human mutation	2003	PMID: 12655544
Tetrahydrobiopterin responsiveness in phenylketonuria. Two new cases and a review of molecular genetic findings.	Lässker U	Journal of inherited metabolic disease	2002	PMID: 11999982
Mental illness in mild PKU responds to biopterin.	Koch R	Molecular genetics and metabolism	2002	PMID: 11914042
A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype.	Guldberg P	American journal of human genetics	1998	PMID: 9634518
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
Molecular basis of phenotypic heterogeneity in phenylketonuria.	Okano Y	The New England journal of medicine	1991	PMID: 2014036
GT to AT transition at a splice donor site causes skipping of the preceding exon in phenylketonuria.	Marvit J	Nucleic acids research	1987	PMID: 3615198
Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene.	DiLella AG	Biochemistry	1986	PMID: 3008810
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH	-	-	-	-
http://www.pahdb.mcgill.ca/	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/a0e84b26-03d1-42c0-a937-859d45d287e0	-	-	-	-
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Text-mined citations for rs5030861 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_000277.3(PAH):c.1315+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs5030861 ...