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_000277.2(PAH):c.977G>A (p.Trp326Ter)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229887

579 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 60780d1e-de33-4990-88af-58b2b28a5fdd

Approved on: 2020-04-13

Published on: 2020-04-13

HGVS expressions

NM_000277.2:c.977G>A

NM_000277.2(PAH):c.977G>A (p.Trp326Ter)

NC_000012.12:g.102844424C>T

CM000674.2:g.102844424C>T

NC_000012.11:g.103238202C>T

CM000674.1:g.103238202C>T

NC_000012.10:g.101762332C>T

NG_008690.1:g.78179G>A

NG_008690.2:g.118987G>A

NM_000277.1:c.977G>A

NM_001354304.1:c.977G>A

NM_000277.3:c.977G>A

NM_001354304.2:c.977G>A

ENST00000307000.7:c.962G>A

ENST00000549247.6:n.736G>A

ENST00000551114.2:n.639G>A

ENST00000553106.5:c.977G>A

ENST00000635477.1:n.81G>A

ENST00000635528.1:n.492G>A

Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"

PVS1 PM3_Very Strong PM2 PP4_Moderate

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.977G>A (p.Trp326Ter) is a variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequencies in ethnically diverse control databases (gnomAD AF 0.00000399; PAH PM2 cutoff: <0.0002) (PM2). It has been identified in at least five PKU cases in whom BH4 deficiency was excluded (PP4_Moderate), in four cases in trans with known pathogenic variants (PM3_VeryStrong). It has been identified in at least two Chinese classic PKU cases (PMID: 261600; PMID: 1301927; PMID: 28982351), in trans with the known pathogenic (per PAH VCEP) p.Y356X and p.R243Q variants; as a single heterozygous variant in a Chinese classic PKU case with BH4 deficiency excluded (PMID: 24705691); in trans with the known pathogenic (per PAH VCEP) p.R261Q variant in one Slovak case with classic PKU with BH4 deficiency said to be excluded (PMID: 23764561); one Chinese proband with mild hyperphenylalanemia in trans with c.1197A>T (p.V399V) (PMID: 25456745). It is also listed Pathogenic in ClinVar by three labs (variant ID 579). Classification: Pathogenic Supporting Criteria: PVS1, PM2; PM3_VeryStrong; PP4_Moderate

PVS1

Nonsense variant (p.W326X)

PM3_Very Strong

It has been identified in at least five PKU cases in whom BH4 deficiency was excluded (PP4_Moderate), in four cases in trans with known pathogenic variants (PM3_VeryStrong). It has been identified in at least two Chinese classic PKU cases (PMID: 261600; PMID: 1301927; PMID: 28982351), in trans with the known pathogenic (per PAH VCEP) p.Y356X and p.R243Q variants; as a single heterozygous variant in a Chinese classic PKU case with BH4 deficiency excluded (PMID: 24705691); in trans with the known pathogenic (per PAH VCEP) p.R261Q variant in one Slovak case with classic PKU with BH4 deficiency said to be excluded (PMID: 23764561); one Chinese proband with mild hyperphenylalanemia in trans with c.1197A>T (p.V399V) (PMID: 25456745). It is also listed Pathogenic in ClinVar by three labs (variant ID 579).

Single patient with HPA PubMed:25456745

PM2

not found in any pop database

PP4_Moderate

BH4 defect excluded PubMed:24705691

BH4 defect excluded PubMed:25456745

Curation History

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