NM_000277.3(PAH):c.913-7A>G AND Phenylketonuria

Germline classification:: Likely pathogenic (7 submissions)
Last evaluated:: Feb 16, 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:: RCV000589029.13

Allele description [Variation Report for NM_000277.3(PAH):c.913-7A>G]

NM_000277.3(PAH):c.913-7A>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.913-7A>G

HGVS:

NC_000012.12:g.102846958T>C
NG_008690.2:g.116453A>G
NM_000277.3:c.913-7A>GMANE SELECT
NM_001354304.2:c.913-7A>G
NC_000012.11:g.103240736T>C
NM_000277.1(PAH):c.913-7A>G
NM_000277.1:c.913-7A>G

Links:

dbSNP: rs62517165

NCBI 1000 Genomes Browser:

rs62517165

Molecular consequence:

NM_000277.3:c.913-7A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001354304.2:c.913-7A>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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000696472	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 18, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23357515, 26322415, 24401910, 10356315, 8981952, 26666653 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000791679	Counsyl	no assertion criteria provided	Likely pathogenic (May 19, 2017)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 12655553, 24048906, 23357515, 16601866, 24350308, 16256386, 23430918, 22513348, 24130151, 10394930, 8981952
SCV000893938	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 12, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001370819	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Feb 16, 2020)	germline	curation	PubMed (10) [See all records that cite these PMIDs] 22513348, 24401910, 24350308, 24048906, 24130151, 26666653, 26322415, 16601866, 9634518, 8981952 Citation Link,
SCV001463132	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001580108	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26600521, 29499199, 29653233, 28492532
SCV004209594	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 7, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

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

Biochemical phenotype and its relationship with genotype in hyperphenylalaninemia heterozygotes.

Mallolas J, Milà M, Lambruschini N, Cambra FJ, Campistol J, Vilaseca MA.

Mol Genet Metab. 1999 Jun;67(2):156-61.

PubMed [citation]

PMID:: 10356315

Mutational spectrum in German patients with phenylalanine hydroxylase deficiency.

Aulehla-Scholz C, Heilbronner H.

Hum Mutat. 2003 Apr;21(4):399-400.

PubMed [citation]

PMID:: 12655553

See all PubMed Citations (21)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696472.1

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

Description

Variant summary: Variant affects a non-conserved nucleotide located in close proximity of an exon-intron boundary. 5/5 in silico tools predict the variant to create a splice acceptor site7 nucleotides upstream of the intron 8/ exon 9 splice junction. The variant was observed in the general population by the ExAC project at an allele frequency of 0.00082% which does not exceed the maximal expected allele frequency of a disease causing PAH allele (~0.8%). It was reported in several PKU/HPA patients with a second pathogenic mutation on the other allele indicating pathogenicity. HGMD lists variant as Pathogenic. Considering all evidence, 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 Counsyl, SCV000791679.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

#	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 Fulgent Genetics, Fulgent Genetics, SCV000893938.2

#	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

From ClinGen PAH Variant Curation Expert Panel, SCV001370819.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (10)

Description

The c.913-7A>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) PMID: 9634518, 16601866. This variant has extremely low frequency in gnomAD (MAF=0.00003). This variant was detected with 10 different variants for a total of 3.75 points (PM3_Strong. Computational evidence predicts splicing changes. 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., SCV001463132.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001580108.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change falls in intron 8 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. This variant is present in population databases (rs62517165, gnomAD 0.003%). This variant has been observed in individual(s) with phenylketonuria (PKU) (PMID: 26600521, 29499199, 29653233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS8-7A>G. ClinVar contains an entry for this variant (Variation ID: 102894). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been 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, SCV004209594.1

#	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

Relating variation to medicine