NM_000277.3(PAH):c.169-13T>G AND Phenylketonuria

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Aug 17, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000778351.14

Allele description

NM_000277.3(PAH):c.169-13T>G

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.169-13T>G

Other names:

NM_000277.2(PAH):c.169-13T>G

HGVS:

NC_000012.12:g.102894931A>C
NG_008690.2:g.68480T>G
NM_000277.3:c.169-13T>GMANE SELECT
NM_001354304.2:c.169-13T>G
NC_000012.11:g.103288709A>C
NM_000277.1:c.169-13T>G

Links:

dbSNP: rs62507341

NCBI 1000 Genomes Browser:

rs62507341

Molecular consequence:

NM_000277.3:c.169-13T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354304.2:c.169-13T>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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MHC class II antigen [Homo sapiens]
MHC class II antigen [Homo sapiens]
gi|2438257296|gb|WCI14691.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000914559	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Dec 6, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19062537, 17935162, 9521426, 30389586, 12655550 Citation Link,
SCV001590611	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 2, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9521426, 30389586, 28492532
SCV002032195	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Aug 17, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 21147011, 9521426 Citation Link,
SCV002088673	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 20, 2017)	germline	clinical testing

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Predicting a clinical/biochemical phenotype for PKU/MHP patients with PAH gene mutations.

Kasnauskiene J, Cimbalistiene L, Kucinskas V.

Genetika. 2008 Oct;44(10):1397-403.

PubMed [citation]

PMID:: 19062537

Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.

Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N.

Hum Mutat. 2008 Jan;29(1):167-75.

PubMed [citation]

PMID:: 17935162

See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000914559.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The PAH c.169-13T>G intron variant has been reported in five studies and is found in a total of seven individuals with phenylalanine hydroxylase deficiency including in six in a compound heterozygous state and in one in a heterozygous state where the second variant could not be identified (Bosco et al. 1998; Kasnauskiene et al. 2003; Kasnauskiene et al. 2008; ZurflÃ¼h et al. 2008; Esfahani et al. 2018). Control data are unavailable for this variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. This is based on one allele only in a region with good coverage, suggesting that this is a rare variant. Authors predict this variant may activate a cryptic splice site, but no supporting evidence is provided (Bosco et al. 1998). Based on the clinical evidence, the c.169-13T>G 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV001590611.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 102611). This variant is also known as IVS2-13T>G. This variant has been observed in individual(s) with phenylketonuria (PMID: 9521426, 30389586). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs62507341, gnomAD 0.0009%). This sequence change falls in intron 2 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen PAH Variant Curation Expert Panel, SCV002032195.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The c.169-13T>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 9521426, PMID: 21147011). This variant has extremely low frequency in gnomAD (MAF=0.00001). This variant was detected with pathogenic variants: IVS10-11G>A (PMID: 21147011); p.L213P (PMID: 9521426); p.R158Q (PMID: 12640344); p.Y356X (c.1068C > G in 1 patient and c.1068C > A in 1 patient, PMID: 30389586). Computational evidence support a deleterious effect on splicing. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002088673.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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