The c.169-2A>G variant has been identified in at least 1 proband with classic PKU (PMID: 24368688). It has been detected in the homozygous form (PMID: 20188615) as well as in trans with the pathogenic variant Gly272Ter (PMID: 24368688). This variant is present at very low allele frequencies; 0.000007993 overall in gnomAD with a MAF of 0.00003267 (1/30612) in the South Asian population. Computational analysis predicts an alteration of the WT acceptor site, most probably affecting splicing, generating a frameshift, and leading to nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP1_Moderate, PP4.
ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.169-2A>G
Germline
Reviewed by expert panel
Help
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Pathogenic
for
Phenylketonuria
Classification is based on the expert panel submission
Aug 2019 by
ClinGen PAH Variant Curation Expert Panel
Help
FDA Recognized Database
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000277.3(PAH):c.169-2A>G
Variation ID: 555212 Accession: VCV000555212.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102894920 (GRCh38) [ NCBI UCSC ] 12: 103288698 (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 Aug 5, 2018 Sep 6, 2025 Aug 26, 2019 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3(PAH):c.169-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_000277.3:c.169-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NM_001354304.2:c.169-2A>G splice acceptor NC_000012.12:g.102894920T>C NC_000012.11:g.103288698T>C NG_008690.2:g.68491A>G - Protein change
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- Other names
- -
- Canonical SPDI
- NC_000012.12:102894919:T:C
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Global minor allele
frequency (GMAF) HelpThe 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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00001
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 | Gene associated with autosomal recessive phenotype | No evidence available |
GRCh38 GRCh37 |
1593 | 1728 | |
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. |
|---|---|---|---|---|
| Pathogenic (7) |
reviewed by expert panel
|
Aug 26, 2019 | RCV000670987.17 |
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. |
Expand all rows
Collapse all rows
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Aug 26, 2019)
C
Contributing to aggregate classification
|
reviewed by expert panel
|
Phenylketonuria
(Autosomal recessive inheritance)
|
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001370795.1 First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
show
The c.169-2A>G variant has been identified in at least 1 proband with classic PKU (PMID: 24368688). It has been detected in the homozygous form (PMID: 20188615) as well as in trans with the pathogenic variant Gly272Ter (PMID: 24368688). This variant is present at very low allele frequencies; 0.000007993 overall in gnomAD with a MAF of 0.00003267 (1/30612) in the South Asian population. Computational analysis predicts an alteration of the WT acceptor site, most probably affecting splicing, generating a frameshift, and leading to nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP1_Moderate, PP4. (less)
Observation: 1
Collection method: curation
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: curation
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Oct 31, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Phenylketonuria |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893955.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Oct 19, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Phenylketonuria
(Autosomal recessive inheritance)
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767866.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
show
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (PKU) (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence (p.(Glu57Valfs*13)). Analysis of patient cells concludes this variant introduces the use of an upstream cryptic acceptor splice site in intron two, resulting in retention of intronic sequence, a frameshift and a premature termination codon (PMID: 20188615). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (2 heterozygotes,0 homozygotes). (SP) 0703 - Another splice variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. A splice variant at the same intron junction (c.169-13T>G) has been reported several times as pathogenic in patients with PKU (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic (ClinVar), and has been observed in a homozygous family, and a compound heterozygous patient with PKU (ClinVar, PMID: 20188615, PMID: 24368688). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
|
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Phenylketonuria
(Autosomal recessive inheritance)
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047580.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
show
This invariant splice site c.169-2A>G has been detected in the homozygous form in proband with classic Phenylketonuria (PKU) (Ho G et al). This variant has allele frequency of 0.00080% in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Abnormal circulating phenylalanine concentration (present) , Seizure (present) , Hypopigmentation of hair (present) , Hypertonia (present) , Abnormal cerebral white matter morphology (present) , Cerebellar atrophy (present)
Comment on clinical features:
Consanguinity: Present Age of onset: 6th day Clinical symptoms and progression: phenylketonuria, seizures, blonde hair, hypertonia in upper and lower limb. Antenatal and birth history: neonatal seizures at 6th day of life. Investigations: MRI brain- t2 flair hyperintensity noted in bilateral periventricular deep white matter , bilateral internal capsule globus pallidus, midbrain cerebellar peduncle showing diffusion.
|
|
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Pathogenic
(Aug 11, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Phenylketonuria |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003441013.3
First in ClinVar: Feb 07, 2023 Last updated: Feb 25, 2025 |
Comment:
show
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 20188615). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that disruption of this splice site alters PAH gene expression (PMID: 20188615). ClinVar contains an entry for this variant (Variation ID: 555212). This variant is also known as c.168-2A>G. Disruption of this splice site has been observed in individual(s) with hyperphenylalaninemia (PMID: 20188615, 29499199, 32668217). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change affects an acceptor splice site in intron 2 of the PAH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 04, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
|
Phenylketonuria |
Revvity Omics, Revvity
Accession: SCV002016503.4
First in ClinVar: Nov 29, 2021 Last updated: Sep 06, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Nov 29, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Phenylketonuria |
Counsyl
Accession: SCV000795919.2
First in ClinVar: Aug 05, 2018 Last updated: Jun 29, 2025 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (PKU) (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence (p.(Glu57Valfs*13)). Analysis of patient cells concludes this variant introduces the use of an upstream cryptic acceptor splice site in intron two, resulting in retention of intronic sequence, a frameshift and a premature termination codon (PMID: 20188615). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (2 heterozygotes,0 homozygotes). (SP) 0703 - Another splice variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. A splice variant at the same intron junction (c.169-13T>G) has been reported several times as pathogenic in patients with PKU (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic (ClinVar), and has been observed in a homozygous family, and a compound heterozygous patient with PKU (ClinVar, PMID: 20188615, PMID: 24368688). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
This invariant splice site c.169-2A>G has been detected in the homozygous form in proband with classic Phenylketonuria (PKU) (Ho G et al). This variant has allele frequency of 0.00080% in the gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 20188615). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that disruption of this splice site alters PAH gene expression (PMID: 20188615). ClinVar contains an entry for this variant (Variation ID: 555212). This variant is also known as c.168-2A>G. Disruption of this splice site has been observed in individual(s) with hyperphenylalaninemia (PMID: 20188615, 29499199, 32668217). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change affects an acceptor splice site in intron 2 of the PAH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The Genetic Landscape and Epidemiology of Phenylketonuria. | Hillert A | American journal of human genetics | 2020 | PMID: 32668217 |
| Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype-phenotype correlation in the Chinese population. | Wang R | Clinica chimica acta; international journal of clinical chemistry | 2018 | PMID: 29499199 |
| 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 |
| Phenylalanine hydroxylase gene mutations in phenylketonuria patients from India: identification of novel mutations that affect PAH RNA. | Bashyam MD | Molecular genetics and metabolism | 2010 | PMID: 20188615 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7cb3c9a2-47a2-4ec3-8c6e-7ab64592450a | - | - | - | - |
Text-mined citations for rs1226613045 ...
HelpThese 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 Sep 07, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.