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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.1:c.842+4A>G

CA16020870

439228 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d91a71b3-b17d-4148-8b40-c1de9c400e78

HGVS expressions

NM_000277.1:c.842+4A>G

NC_000012.12:g.102852811T>C

CM000674.2:g.102852811T>C

NC_000012.11:g.103246589T>C

CM000674.1:g.103246589T>C

NC_000012.10:g.101770719T>C

NG_008690.1:g.69792A>G

NG_008690.2:g.110600A>G

NM_000277.2:c.842+4A>G

NM_001354304.1:c.842+4A>G

NM_000277.3:c.842+4A>G

ENST00000307000.7:c.827+4A>G

ENST00000549247.6:n.601+4A>G

ENST00000553106.5:c.842+4A>G

ENST00000635477.1:n.3+4A>G

Likely Pathogenic

PP4_Moderate PP3 PM3 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PP3: HSF: Broken WT Donor Site, New Donor Site. MaxEnt: Broken WT Donor Site.; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4_Moderate: IVS7+4A>G seen in 2 PKU patients. BH4 deficiency was ruled out. Upgraded per ClinGen PAH EP. (PMID:21147011); PM3: Detected in trans with A300S, pathogenic in ClinVar (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM2, PP4_Moderate, PM3).

PP4_Moderate

IVS7+4A>G seen in 2 PKU patients. BH4 deficiency was ruled out. Upgraded per ClinGen PAH EP.

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). IVS7+4A>G seen in 2 patients. PubMed:21147011

PP3

HSF: Broken WT Donor Site, New Donor Site. MaxEnt: Broken WT Donor Site.

PM3

Detected in trans with A300S, pathogenic in ClinVar

Seen in 2 patients in with A300S (VarID 92751, Pathogenic) PubMed:21147011

PM2

Absent from ExAC, gnomAD, 1000G, ESP

Approved on: 2018-08-12

Published on: 2019-04-05

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