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NM_000277.3(PAH):c.914_1199+1del AND Phenylketonuria

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jul 25, 2021
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:
RCV001789825.1

Allele description [Variation Report for NM_000277.3(PAH):c.914_1199+1del]

NM_000277.3(PAH):c.914_1199+1del

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.3(PAH):c.914_1199+1del
Other names:
NM_001354304.2:c.914_1199+1del
HGVS:
  • NC_000012.12:g.102843648_102846953del
  • NG_008690.2:g.116461_119766del
  • NM_000277.3:c.914_1199+1delMANE SELECT
  • NM_001354304.2:c.914_1199+1del
  • NC_000012.11:g.103237426_103240731del
Molecular consequence:
  • NM_000277.3:c.914_1199+1del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354304.2:c.914_1199+1del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_000277.3:c.914_1199+1del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354304.2:c.914_1199+1del - 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

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002032224ClinGen PAH Variant Curation Expert Panel
reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)		Likely pathogenic
(Jul 25, 2021) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV002032224.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The g.~6.7kbdel (p.Ex9_11del; c.914_1199+1del; CA251545) in PAH is a large deletion involving exons 9, 10, and 11. The deletion removed exons 9-11 but spared exon 12 in long-range PCR (see PMID: 10472529). This region is critical to protein function, as exons 9 and 10 form part of the PAH catalytic domain, and include key amino acid residues. Therefore, this is a multi-exon deletion that disrupts the reading frame and is NOT predicted to undergo NMD, which truncates/alters a critical region for protein function. Thus, PVS1_Strong is applied. It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in one case with mild PKU (per abnormal blood Phe levels; BH4 deficiency does not appear to have been formally excluded) (PP4), in confirmed trans with the p.E390G variant (Likely Pathogenic per PAH VCEP) (PMID: 10472529) (PM3). Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3; PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 23, 2022