NM_000277.3(PAH):c.1200-2A>G AND Phenylketonuria

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Aug 10, 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:: RCV001069317.13

Allele description [Variation Report for NM_000277.3(PAH):c.1200-2A>G]

NM_000277.3(PAH):c.1200-2A>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.1200-2A>G

HGVS:

NC_000012.12:g.102840517T>C
NG_008690.2:g.122894A>G
NM_000277.3:c.1200-2A>GMANE SELECT
NM_001354304.2:c.1200-2A>G
NC_000012.11:g.103234295T>C
NM_000277.1:c.1200-2A>G

Links:

dbSNP: rs1592945607

NCBI 1000 Genomes Browser:

rs1592945607

Molecular consequence:

NM_000277.3:c.1200-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001354304.2:c.1200-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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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L110P[VARNAME] (40)
ClinVar
Chain I, kDa heat shock protein, mitochondrial
Chain I, kDa heat shock protein, mitochondrial
gi|816044728|pdb|4PJ1|I

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001234477	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 17, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21890392, 24301756, 16199547, 1301187, 9634518, 28492532
SCV002032199	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Aug 10, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 21147011, 24301756 Citation Link,
SCV002088620	Natera, Inc.	no assertion criteria provided	Pathogenic (Aug 13, 2020)	germline	clinical testing
SCV004813545	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 9, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21147011, 30159852, 21890392 Citation Link,
SCV005053824	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 21, 2024)	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

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.

Eisensmith RC, Woo SL.

Hum Mutat. 1992;1(1):13-23. Review.

PubMed [citation]

PMID:: 1301187

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001234477.5

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

Description

This variant is also known as IVS11-2A>G. 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: 862570). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 21890392, 24301756). 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 an acceptor splice site in intron 11 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 ClinGen PAH Variant Curation Expert Panel, SCV002032199.1

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

Description

The c.1200-2A>G variant in PAH is a null variant (canonical - 2 splice site); Loss of function is a known mechanism of disease, exon skipping disrupts reading frame and is predicted to undergo NMD (not located in last 50bp of preliminary exon). Coding exon 12/13 is present in biologically-relevant transcript. This variant has been reported in 2 individuals with PKU (BH4 deficiency excluded, PMID: 21147011, 24301756). This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, 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 Natera, Inc., SCV002088620.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813545.1

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

Description

Variant summary: PAH c.1200-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251396 control chromosomes (gnomAD). c.1200-2A>G has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; Dobrowolski_2011, Kostandyan_2011, Shirzadeh_2018), and one was reported as compound heterozygous with another pathogenic variant. These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21890392, 30159852, 21147011). ClinVar contains an entry for this variant (Variation ID: 862570). Three submitters have classified the variant as pathogenic, including a ClinGen expert panel. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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, SCV005053824.1

#	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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