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.556del (p.Thr186fs)

CA229620

102733 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: be6afbf7-7d94-4d1e-8fbe-f589dc1fe21b

HGVS expressions

NM_000277.3:c.556del

NM_000277.3(PAH):c.556del (p.Thr186fs)

NC_000012.12:g.102855289del

CM000674.2:g.102855289del

NC_000012.11:g.103249067del

CM000674.1:g.103249067del

NC_000012.10:g.101773197del

NG_008690.1:g.67317del

NG_008690.2:g.108125del

NM_000277.1:c.556del

NM_000277.2:c.556del

NM_001354304.1:c.556del

NM_001354304.2:c.556del

ENST00000307000.7:c.541del

ENST00000549111.5:n.652del

ENST00000551988.5:n.577del

ENST00000553106.5:c.556del

Pathogenic

PM3_Supporting PP4 PM2 PVS1

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.556del (p.Thr186fs) variant in PAH has been observed in two patients with non-PKU hyperphenylalaninemia, with pathogenic variant p.Arg408Trp, phase unknown (PMID: 23357515). This variant is absent from controls in population databases. This is a predicted null frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Supporting, and PP4.

PM3_Supporting

p.[Arg408Trp]; [Thr186Hisfs*9]. Segregation analysis was not done, so phase is unknown. PMID: 23357515

PP4

This variant was observed in two probands with non-PKU HPA (Phe 120-600 µmol/L). It is not mentioned if 6R-BH4 is ruled out. PMID: 23357515

PubMed:23357515

PM2

This variant is absent from controls in ExAC and 1000 Genomes.

PVS1

This is a frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. The exon is present in biologically-relevant transcripts. Loss of function is a known mechanism of disease: 175 pathogenic null variants reported in Clinvar across 13 different exons, 22 of which are in exon 6.

Approved on: 2020-10-15

Published on: 2020-10-15

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