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]

Variant: NM_000277.2(PAH):c.837delC (p.Glu280Asnfs)

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CA267677

120288 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bcdf79d7-d9f1-457f-a01b-cace787307e1

Approved on: 2019-07-14

Published on: 2019-07-14

HGVS expressions

NM_000277.2:c.837del

NM_000277.2(PAH):c.837delC (p.Glu280Asnfs)

NC_000012.12:g.102852824del

CM000674.2:g.102852824del

NC_000012.11:g.103246602del

CM000674.1:g.103246602del

NC_000012.10:g.101770732del

NG_008690.1:g.69783del

NG_008690.2:g.110591del

NM_000277.1:c.837del

NM_001354304.1:c.837del

NM_000277.3:c.837del

ENST00000307000.7:c.822del

ENST00000549247.6:n.596del

ENST00000553106.5:c.837del

Pathogenic

PVS1 PP4 PM3 PM2

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.837del frameshift variant has been identified in at least 2 probands with classic PKU, BH4 deficiency not excluded (PMIDs: 10598814, 26666653). It has been detected in trans with pathogenic variants V388M (PMID: 10598814) and c.1315+1G>A (PMID: 26666653). This variant is absent from 1000G, Exac, and gnomAD databases. C.837delC generates a frameshift predicted to result in a premature stop codon 61 residues downstream in exon 10 and undergo NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP4.

PVS1

c.837delC generates a frameshift predicted to result in a premature stop codon 61 residues downstream in exon 10 and undergo NMD.

PP4

Two compound heterozygous probands have been described with the c.837del variant each with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded.

A compound heterozygous proband with the c.837del variant was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded. PubMed:10598814

A compound heterozygous proband with the c.837del variant (misidentified in this publication as His280Asnfs*61) was described with the classic PKU phenotype and PHE >1200umol/L. Defects in BH4 cofactor metabolism were not excluded. PubMed:26666653

PM3

The c.837del frameshift variant has been observed in trans with pathogenic variants Val388Met (ClinVar 619, Pathogenic) and c.1315+1G>A (ClinVar 576, Pathogenic).

The c.837del frameshift variant was observed in trans with the pathogenic variant Val388Met (ClinVar 619, Pathogenic). PubMed:10598814

The c.837del frameshift variant (in this publication misidentified as His280Asnfs*61) was observed in trans with the pathogenic variant c.1315+1G>A (ClinVar 576, Pathogenic). PubMed:26666653

PM2

Absent from gnomAD, ExAC, and 1000 Genomes.

Curation History

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