NM_000277.3(PAH):c.168+1G>A AND Phenylketonuria

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 9, 2018
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:: RCV000169163.16

Allele description [Variation Report for NM_000277.3(PAH):c.168+1G>A]

NM_000277.3(PAH):c.168+1G>A

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.168+1G>A

Other names:

NM_000277.2(PAH):c.168+1G>A

HGVS:

NC_000012.12:g.102912790C>T
NG_008690.2:g.50621G>A
NM_000277.3:c.168+1G>AMANE SELECT
NM_001354304.2:c.168+1G>A
NC_000012.11:g.103306568C>T
NM_000277.1:c.168+1G>A

Links:

dbSNP: rs62514898

NCBI 1000 Genomes Browser:

rs62514898

Molecular consequence:

NM_000277.3:c.168+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354304.2:c.168+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

Recent activity

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DC153877 Xenopus tropicalis embryo gastrula Xenopus tropicalis cDNA clone rst70h...
DC153877 Xenopus tropicalis embryo gastrula Xenopus tropicalis cDNA clone rst70h16 3', mRNA sequence
gi|119136665|gnl|dbEST|43401619|dbj 3877.1|

Nucleotide
JGI_CABH7262.fwd NIH_XGC_tropSkeMus1 Xenopus tropicalis cDNA clone IMAGE:7850274...
JGI_CABH7262.fwd NIH_XGC_tropSkeMus1 Xenopus tropicalis cDNA clone IMAGE:7850274 5', mRNA sequence
gi|73774831|gnl|dbEST|31030046|gb|D 34.1|

Nucleotide
BJ619197 NIBB Mochii normalized Xenopus early gastrula library Xenopus laevis cD...
BJ619197 NIBB Mochii normalized Xenopus early gastrula library Xenopus laevis cDNA clone XL188g14 5', mRNA sequence
gi|37257713|gnl|dbEST|19924208|dbj| 197.1|

Nucleotide
CR581365 XGC-tailbud-head Xenopus tropicalis cDNA clone THdA025m06 5', mRNA sequ...
CR581365 XGC-tailbud-head Xenopus tropicalis cDNA clone THdA025m06 5', mRNA sequence
gi|50468791|gnl|dbEST|24666573|emb| 365.1|

Nucleotide
JGI_XZG26597.rev NIH_XGC_tropGas7 Xenopus tropicalis cDNA clone IMAGE:7542243 3'...
JGI_XZG26597.rev NIH_XGC_tropGas7 Xenopus tropicalis cDNA clone IMAGE:7542243 3', mRNA sequence
gi|57264890|gnl|dbEST|27070921|gb|C 58.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220391	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Jun 6, 2014)	unknown	literature only	PubMed (2) [See all records that cite these PMIDs] 18299955, 8807331 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000886558	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Dec 9, 2018)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 24368688, 18294361, 8807331 Citation Link,
SCV001590612	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 7, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8807331, 24368688, 16199547, 1301187, 9634518, 28492532
SCV002088676	Natera, Inc.	no assertion criteria provided	Pathogenic (Dec 14, 2019)	germline	clinical testing
SCV004201364	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 31, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only

Citations

PubMed

Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.

Bercovich D, Elimelech A, Zlotogora J, Korem S, Yardeni T, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y.

J Hum Genet. 2008;53(5):407-418. doi: 10.1007/s10038-008-0264-4. Epub 2008 Feb 26.

PubMed [citation]

PMID:: 18299955

A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population.

Bercovich D, Elimelech A, Yardeni T, Korem S, Zlotogora J, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y.

Ann Hum Genet. 2008 May;72(Pt 3):305-9. doi: 10.1111/j.1469-1809.2007.00425.x. Epub 2008 Feb 19.

PubMed [citation]

PMID:: 18294361

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000220391.2

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

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

From ClinGen PAH Variant Curation Expert Panel, SCV000886558.2

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

Description

The c.168+1G>A variant in PAH is at a canonical splice site at intron 3, and is absent in all population databases. It has been identified in trans with a pathogenic variant (Ho, 2014), and as a homozygous variant (PMID: 18294361) in patients with phenylketonuria. Defects in BH4 metabolism were excluded as a cause of elevated phenylalanine in two patients (PMID: 24368688, 8807331). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4_Moderate.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001590612.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

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: 102604). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 8807331, 24368688). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518).

#	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., SCV002088676.1

#	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

From Baylor Genetics, SCV004201364.2

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

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

Last Updated: Sep 29, 2024

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