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_000277.2(PAH):c.839_840insT (p.Glu280Aspfs)

CA229810

102867 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 44b9a940-234d-4ed7-911c-55dac5f90d77

HGVS expressions

NM_000277.2:c.839_840insT

NM_000277.2(PAH):c.839_840insT (p.Glu280Aspfs)

NC_000012.12:g.102852817_102852818insA

CM000674.2:g.102852817_102852818insA

NC_000012.11:g.103246595_103246596insA

CM000674.1:g.103246595_103246596insA

NC_000012.10:g.101770725_101770726insA

NG_008690.1:g.69785_69786insT

NG_008690.2:g.110593_110594insT

ENST00000553106.6:c.839_840insT

ENST00000307000.7:c.824_825insT

ENST00000549247.6:n.598_599insT

ENST00000553106.5:c.839_840insT

NM_000277.1:c.839_840insT

NM_001354304.1:c.839_840insT

NM_000277.3:c.839_840insT

NM_001354304.2:c.839_840insT

NM_000277.3(PAH):c.839_840insT (p.Glu280fs)

Pathogenic

PM2_Supporting PVS1 PP4

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.839_840insT (p.Glu280Aspfs) variant in PAH has been reported in an individual with PKU (PP4; 15300621). This variant has is absent from ExAC and gnomAD (PM2_supporting). It is a null variant (frameshift) in exon 7/13 with NMD predicted (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4.

PM2_Supporting

Absent from controls in ExAC and gnomAD v2.1.1

PVS1

Null variant (frameshift) in exon 7/13. This variant is an insertion of a T between coding positions 839 and 840. This leads to a change from glutamic acid to aspartic acid at position 280, followed by a threonine and then premature stop codon. NMD predicted.

PP4

280insT was detected in a PKU patient. PMID: 15300621

The PAH genes from 40 phenylketonuria (PKU) patients and 30 normal controls were screened by PCR-single strand conformation polymorphism (SSCP) and further sequencing. 280insT was detected. No abnormalities in the PAH gene from 30 controls were detected. PubMed:15300621

Approved on: 2023-10-15

Published on: 2023-10-15

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