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_001354304.2:c.560G>A

CA16020817

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a04e00a4-aa68-42af-8b3a-dc3540df0c32

Approved on: 2024-02-23

Published on: 2024-07-16

HGVS expressions

NM_001354304.2:c.560G>A

NC_000012.12:g.102855282C>T

CM000674.2:g.102855282C>T

NC_000012.11:g.103249060C>T

CM000674.1:g.103249060C>T

NC_000012.10:g.101773190C>T

NG_008690.1:g.67321G>A

NG_008690.2:g.108129G>A

ENST00000553106.6:c.560G>A

ENST00000307000.7:c.545G>A

ENST00000549111.5:n.656G>A

ENST00000551988.5:n.581G>A

ENST00000553106.5:c.560G>A

NM_000277.1:c.560G>A

NM_000277.2:c.560G>A

NM_001354304.1:c.560G>A

NM_000277.3:c.560G>A

Pathogenic

PVS1 PP4_Moderate PM2_Supporting

PM3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.560G>A (p.Trp187Ter) variant in PAH is a nonsense variant in exon 6 of 13 predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). It was reported in a patient from Korea with mild hyperphenylalaninemia, detected with pathogenic variant c.1068C>A p.Tyr356X, phase unknown (PMID: 18985011; PP4_M); however, the VCEP is concerned that these variants are in cis due to genotype (2 LoF variants) discrepant with clinical phenotype (MHP). So we are not applying PM3 evidence. This variant is absent from gnomAD. In summary, this variant meets the criteria to be classified as pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PVS1, PM2_supporting, PP4_moderate.

PVS1

Nonsense variant in exon 6/13 predicted to undergo NMD.

PP4_Moderate

Detected in a patient with MHP (plasma Phe 177), Urinary pterin analyses and dihydropteridine reductase (DHPR) assays were performed to exclude 6-pyruvoyltetrahydropterin synthase (PTPS) deficiencies. PMID: 18985011

PM2_Supporting

Absent from gnomAD

PM3

Detected with c.1068C>A p.Tyr356X (P by 8 submitters), phasing unknown. VCEP is concerned that these variants are in cis due to genotype (2 LoF variants) discrepant with clinical phenotype (MHP). So PM3 is not applied for this unphased evidence.

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