Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_000277.1:c.510-19_667del

CA16020833

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7a382923-29c1-41c1-a7b6-c331affb9e93

HGVS expressions

NM_000277.1:c.510-19_667del

NC_000012.12:g.102855177_102855353del

CM000674.2:g.102855177_102855353del

NC_000012.11:g.103248955_103249131del

CM000674.1:g.103248955_103249131del

NC_000012.10:g.101773085_101773261del

NG_008690.1:g.67252_67428del

NG_008690.2:g.108060_108236del

ENST00000553106.6:c.510-19_667del

ENST00000307000.7:c.495-19_652del

ENST00000549111.5:n.606-19_763del

ENST00000553106.5:c.510-19_667del

NM_000277.2:c.510-19_667del

NM_001354304.1:c.510-19_667del

NM_000277.3:c.510-19_667del

NM_001354304.2:c.510-19_667del

Pathogenic

PP4 PVS1 PM3_Supporting PM2_Supporting

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.510-19_667del variant in PAH involves part of exon 6, predicted to result in frameshift and NMD (PVS1). It has been reported in 1 individual with PKU. (PP4; PMID: 23842451). This variant is absent from gnomAD (PM2_supporting). This variant was detected with p.G272* (Pathogenic in ClinVar; PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PM3_supporting, PP4.

PP4

c.510-21_665del was detected in one patient with Phe level 855. BH4 deficiency not reported/assessed. PMID: 23842451

Data were collected from 183 patients in six Dutch university medical centres. Blood Phe concentrations in dried blood spots were measured by the patients’ respective centre laboratory according to standard quantitative methods, with the same method per patient. c.510-21_665del was detected in one patient with Phe level 855 at baseline (T=0). PubMed:23842451

PVS1

Partial exon deletion: His170, c.665 is codon 222 (Asp) HSF: Alteration of the WT acceptor site, most probably affecting splicing. MaxENT: 280-700% variation. Overlap with coding exons and predicted to undergo NMD: results in frameshift, percentage of exonic region overlapped: 11.63% (158/1359)

PM3_Supporting

Detected with G272*, Pathogenic in ClinVar. Parental confirmation not reported.

Patient genotype: c.510-21_665del/G272* (VarID 596, Pathogenic) PubMed:23842451

PM2_Supporting

Absent from ExAC, gnomAD, 1000G, ESP

Approved on: 2023-12-30

Published on: 2023-12-30

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