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_000277.3(PAH):c.1198del (p.Arg400fs)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229383

102554 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 75e839da-2e8d-49ff-8ffe-705df7accf8d

Approved on: 2021-05-29

Published on: 2021-05-29

HGVS expressions

NM_000277.3:c.1198del

NM_000277.3(PAH):c.1198del (p.Arg400fs)

ENST00000553106.6:c.1198del

ENST00000307000.7:c.1183del

ENST00000549247.6:n.957del

ENST00000551114.2:n.860del

ENST00000553106.5:c.1198del

ENST00000635477.1:n.302del

ENST00000635528.1:n.713del

NM_000277.1:c.1198del

NM_000277.2:c.1198del

NM_001354304.1:c.1198del

NM_001354304.2:c.1198del

NC_000012.12:g.102843648del

CM000674.2:g.102843648del

NC_000012.11:g.103237426del

CM000674.1:g.103237426del

NC_000012.10:g.101761556del

NG_008690.1:g.78956del

NG_008690.2:g.119764del

Pathogenic

PM3_Strong PP4 PM2 PVS1_Strong

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1198del (p.Arg400fs) variant in PAH has been detected in 1 patient from the Northeastern US, serum Phe > 240umol/L; BH4 deficiency not excluded (PMID: 8659548; PP4). This variant was detected with c.168+1G>A and I65T, both reported as pathogenic in ClinVar and confirmed in trans (2.0points; PM3_Strong). This frameshift variant is not predicted to undergo NMD, located in intron 11-12 out of 13 total exons (11 out of total exons) (PVS1_Strong), and this variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_Strong, PM2, PP4, PM3_Strong.

PM3_Strong

PMID: 8807331 - R400fs detected with c.168+1G>A - reported as Pathogenic in ClinVar (VarID:102604; 3 submitters), phase confirmed - 1.0 points; PMID: 7726156 - R400fs detected with I65T, reported as Pathogenic in ClinVar (VarID:636; 15 submitters); phase confirmed - 1.0points

PP4

PMID: 8659548 - R400fs detected in 1 patient from the Northeastern US, serum Phe > 240umol/L; BH4 deficiency not excluded

PM2

Variant absent from population databases.

PVS1_Strong

Frameshift variant, not predicted to undergo NMD, located in last exon or last 50bp of preliminary exon, stop codon at position 451 in exon 13. Expected to disrupt the last 53 amino acids of the PAH protein

Curation History

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