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_000277.3(PAH):c.941del (p.Pro314fs)

CA229866

102906 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e27280b9-e470-4ae1-a0ea-56e2782d634d

HGVS expressions

NM_000277.3:c.941del

NM_000277.3(PAH):c.941del (p.Pro314fs)

NC_000012.12:g.102846924del

CM000674.2:g.102846924del

NC_000012.11:g.103240702del

CM000674.1:g.103240702del

NC_000012.10:g.101764832del

NG_008690.1:g.75680del

NG_008690.2:g.116488del

ENST00000553106.6:c.941del

ENST00000307000.7:c.926del

ENST00000549247.6:n.700del

ENST00000551114.2:n.603del

ENST00000553106.5:c.941del

ENST00000635477.1:n.74-2492del

ENST00000635528.1:n.456del

NM_000277.1:c.941del

NM_000277.2:c.941del

NM_001354304.1:c.941del

NM_001354304.2:c.941del

Pathogenic

PVS1 PP4 PM2 PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The frameshift variant c.941del (HGVS nomenclature c.940del) occurs in exon 9 of 13 and is predicted to result in NMD. The variant is absent from population databases, including gnomAD. One classical PKU patient has been reported (PMID: 9600453) with this variant in trans with c.1066-11G>A (ClinVar 607, Pathogenic with expert panel review). In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.

PVS1

The c.941del variant in exon 9 results in the p.Pro314LeufsTer27 frameshift which creates a premature stop codon in exon 10 of 13. This is predicted to result in NMD.

PP4

Patient F536 of PMID: 9600453 has a classical PKU phenotype with Phe levels at diagnosis higher than 20 mg/dl.

PM2

Variant is absent from population databases including gnomAD, ExAC, 1000 Genomes, and ESP.

PM3

Patient F536 of PMID: 9600453 is compound heterozygous for c.941del and c.1066-11G>A (ClinVar 607, Pathogenic with expert panel review).

Approved on: 2022-06-12

Published on: 2022-06-12

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