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.592_613del (p.Tyr198fs)

CA229638

102746 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 036d6752-4402-4d61-a809-9bd39f41162a

HGVS expressions

NM_000277.3:c.592_613del

NM_000277.3(PAH):c.592_613del (p.Tyr198fs)

NC_000012.12:g.102855231_102855252del

CM000674.2:g.102855231_102855252del

NC_000012.11:g.103249009_103249030del

CM000674.1:g.103249009_103249030del

NC_000012.10:g.101773139_101773160del

NG_008690.1:g.67353_67374del

NG_008690.2:g.108161_108182del

ENST00000553106.6:c.592_613del

ENST00000307000.7:c.577_598del

ENST00000549111.5:n.688_709del

ENST00000553106.5:c.592_613del

NM_000277.1:c.592_613del

NM_000277.2:c.592_613del

NM_001354304.1:c.592_613del

NM_001354304.2:c.592_613del

Pathogenic

PM3_Strong PM2 PVS1 PP4_Moderate

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen PAH Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.592_613del (p.Tyr198fs) variant in PAH is a frameshift variant predicted to cause termination at amino acid 334 in exon 10, resulting in nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. It has been detected in multiple patients with PAH deficiency with pathogenic variants: c.782G>A (p.Arg261Gln) (PMID: 21890392); c.1222C>T (p.Arg408Trp) (PMID:26481238); c.969+1G>A (IVS9 + 1G>A) (PMID:18321666); c.311C>A (p.A104D), c.755G>A (p.R252Q) (PMID:23942198). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PM3_strong, PP4_moderate, PVS1

PM3_Strong

Detected with pathogenic variants (3.25 point): c.782G>A (p.Arg261Gln) in trans in PMID: 21890392; c.1222C>T (p.Arg408Trp) in trans in 26481238; c.969+1G>A (IVS9 + 1G>A) LP, phase unconfirmed in 18321666; c.311C>A (p.A104D), c.755G>A (p.R252Q) phase unconfirmed in 23942198;

PM2

Absent from controls in gnomAD, ExAC, 1000 Genomes, or ESP.

PVS1

This is a frameshift variant with termination predicted at amino acid 334 which is predicted to undergo NMD.

PP4_Moderate

Detected in multiple patients with PAH deficiency, PAH, GCH1, PTS, and QDP sequenced PMID: 23942198

Approved on: 2023-03-16

Published on: 2023-03-16

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