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_000277.3(PAH):c.911A>G (p.Gln304Arg)

CA229844

102891 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 21c2bc7f-f607-4bc1-a133-2c31f1d3b1db

HGVS expressions

NM_000277.3:c.911A>G

NM_000277.3(PAH):c.911A>G (p.Gln304Arg)

ENST00000553106.6:c.911A>G

ENST00000307000.7:c.896A>G

ENST00000549247.6:n.670A>G

ENST00000551114.2:n.573A>G

ENST00000553106.5:c.911A>G

ENST00000635477.1:n.72A>G

NM_000277.1:c.911A>G

NM_000277.2:c.911A>G

NM_001354304.1:c.911A>G

NM_001354304.2:c.911A>G

NC_000012.12:g.102851688T>C

CM000674.2:g.102851688T>C

NC_000012.11:g.103245466T>C

CM000674.1:g.103245466T>C

NC_000012.10:g.101769596T>C

NG_008690.1:g.70915A>G

NG_008690.2:g.111723A>G

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3_Supporting

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.911A>G (p.Gln304Arg) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 8632937, 22841515, 30747360). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant p.R252W (PM3_supporting). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3.

PP4_Moderate

detected in 3 patients, one with severe PKU (PMID: 8632937, 22841515); 1 with classical PKU BH4 deficiency ruled out (PMID: 30747360)

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.98

PM2

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

PM3_Supporting

Detected with pathogenic variant R252W (5 submitters); parental analysis not reported

Approved on: 2019-12-14

Published on: 2021-05-14

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