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.931_932delCT (p.Leu311Glyfs)

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CA267689

120297 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 23b3c015-0c55-4a60-a3f3-0d297d4a1b9d

Approved on: 2019-07-14

Published on: 2019-07-14

HGVS expressions

NM_000277.2:c.931_932del

NM_000277.2(PAH):c.931_932delCT (p.Leu311Glyfs)

NC_000012.12:g.102846936_102846937del

CM000674.2:g.102846936_102846937del

NC_000012.11:g.103240714_103240715del

CM000674.1:g.103240714_103240715del

NC_000012.10:g.101764844_101764845del

NG_008690.1:g.75670_75671del

NG_008690.2:g.116478_116479del

NM_000277.1:c.931_932del

NM_001354304.1:c.931_932del

NM_000277.3:c.931_932del

ENST00000307000.7:c.916_917del

ENST00000549247.6:n.690_691del

ENST00000551114.2:n.593_594del

ENST00000553106.5:c.931_932del

ENST00000635477.1:n.74-2502_74-2501del

ENST00000635528.1:n.446_447del

Pathogenic

PVS1 PP4 PM3_Supporting PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.931_932del frameshift variant has been identified in at least 1 proband with mild PKU, BH4 deficiency not excluded (PMID: 26666653). It has been detected in trans with the pathogenic variant R241C (PMID: 26666653). This variant is absent from 1000G, Exac, and gnomAD databases. c.931_932delCT generates a frameshift predicted to result in a premature stop codon 4 residues downstream in exon 9 and undergo NMD. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3_Supporting, PM2, PP4.

PVS1

c.931_932delCT generates a frameshift predicted to result in a premature stop codon 4 residues downstream in exon 9 and undergo NMD.

PP4

A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 < Phe < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded.

A compound heterozygous proband with the c.931_932del variant was described with a mild PKU phenotype and 600 < Phe < 1200 umol/L. Defects in BH4 cofactor metabolism were not excluded. PubMed:26666653

PM3_Supporting

The c.931_932del frameshift variant was observed in trans with the pathogenic variant Arg241Cys (ClinVar 102803, Pathogenic). Parental testing was not performed. PubMed:26666653

PM2

Absent from gnomAD, ExAC, and 1000 Genomes.

Curation History

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