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NM_000277.3(PAH):c.510-735_912+434del AND Phenylketonuria

Clinical significance:Pathogenic (Last evaluated: Jun 5, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001375904.1

Allele description [Variation Report for NM_000277.3(PAH):c.510-735_912+434del]

NM_000277.3(PAH):c.510-735_912+434del

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.3(PAH):c.510-735_912+434del
HGVS:
  • NC_000012.12:g.102851253_102856067del
  • NG_008690.2:g.107344_112158del
  • NM_000277.3:c.510-735_912+434delMANE SELECT
  • NM_001354304.2:c.510-735_912+434del
  • NC_000012.11:g.103245031_103249845del
Molecular consequence:
  • NM_000277.3:c.510-735_912+434del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001354304.2:c.510-735_912+434del - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_000277.3:c.510-735_912+434del - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001354304.2:c.510-735_912+434del - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001572871ClinGen PAH Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Jun 5, 2020)
germlinecuration

Citation Link

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, SCV001572871.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The p.Ex6_7_8del (c.510-735_912+434del) variant is a 4799bp deletion in PAH, a gene where loss of function is a known disease mechanism, and is predicted to lead to a frameshift at Gly171, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD (structural variant version, gnomAD SVs v2.1) (PM2). It has been previously reported in one patient with PKU (BH4 deficiency excluded by sequencing of the genes in the BH4 cofactor metabolism pathway) (PP4_Moderate) (PMID: 23942198) in presumed trans with the p.F55L variant (Pathogenic per PAH VCEP) (0.5 points; PM3_Supporting). Classification: Pathogenic Supporting Criteria: PVS1; PM2; PP4_Moderate; PM3_Supporting

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

Last Updated: Apr 23, 2022