NM_000277.3(PAH):c.1199+2T>G AND Phenylketonuria

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 16, 2023
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:: RCV000673497.2

Allele description [Variation Report for NM_000277.3(PAH):c.1199+2T>G]

NM_000277.3(PAH):c.1199+2T>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.1199+2T>G

HGVS:

NC_000012.12:g.102843644A>C
NG_008690.2:g.119767T>G
NM_000277.3:c.1199+2T>GMANE SELECT
NM_001354304.2:c.1199+2T>G
NC_000012.11:g.103237422A>C
NM_000277.1:c.1199+2T>G

Links:

dbSNP: rs62508737

NCBI 1000 Genomes Browser:

rs62508737

Molecular consequence:

NM_000277.3:c.1199+2T>G - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001354304.2:c.1199+2T>G - 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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hypothetical protein Naga_100081g21 [Nannochloropsis gaditana]
hypothetical protein Naga_100081g21 [Nannochloropsis gaditana]
gi|585101001|gb|EWM21003.1||gnl|WGS |Naga_100081g21.750

Protein
Oregano - LiverTox
Oregano - LiverTox
PGM3 [Aquila chrysaetos chrysaetos]
PGM3 [Aquila chrysaetos chrysaetos]
Gene ID:115349684

Gene
CHS2 [Candida albicans SC5314]
CHS2 [Candida albicans SC5314]
Gene ID:3641893

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000798705	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Mar 20, 2018)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11161825, 25863075 Citation Link,
SCV004015329	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Mar 16, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000798705

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Mar 20, 2018)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004015329

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Likely pathogenic
(Mar 16, 2023)

germline

curation

Citation Link

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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	curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterization of the mouse phenylalanine hydroxylase mutation Pah(enu3).

Haefele MJ, White G, McDonald JD.

Mol Genet Metab. 2001 Jan;72(1):27-30.

PubMed [citation]

PMID:: 11161825

[Mutations of phenylalanine hydroxylase gene detected in 20 patients with phenylketonuria from Yunnan Province].

Tang X, Chen H, Zhang Y, Li L, Mi H, Xu Q, Zhu B.

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2015 Apr;32(2):153-7. doi: 10.3760/cma.j.issn.1003-9406.2015.02.001. Chinese.

PubMed [citation]

PMID:: 25863075

Details of each submission

From Counsyl, SCV000798705.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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, SCV004015329.1

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

Description

The c.1199+2T>G variant in PAH occurs within the canonical splice donor of intron 11. It is predicted to cause skipping of biologically-relevant exon 11, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. This variant may be reported in the literature (PMID: 25863075), but is unavailable for evaluation. Sequence analysis of a PKU mouse model with this variant revealed two cryptic splice donor sites, upstream and downstream of the wild-type splice site (PMID: 11161825). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PVS1

#	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: Jul 29, 2023

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