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_000277.2(PAH):c.473G>C (p.Arg158Pro)

CA229571

102694 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4e4301cb-1d43-4b70-9923-1aceceb5a6cf

HGVS expressions

NM_000277.2:c.473G>C

NM_000277.2(PAH):c.473G>C (p.Arg158Pro)

NC_000012.12:g.102866632C>G

CM000674.2:g.102866632C>G

NC_000012.11:g.103260410C>G

CM000674.1:g.103260410C>G

NC_000012.10:g.101784540C>G

NG_008690.1:g.55971G>C

NG_008690.2:g.96779G>C

NM_000277.1:c.473G>C

NM_001354304.1:c.473G>C

NM_000277.3:c.473G>C

NM_001354304.2:c.473G>C

ENST00000307000.7:c.458G>C

ENST00000549111.5:n.569G>C

ENST00000551988.5:n.530+10830G>C

ENST00000553106.5:c.473G>C

Uncertain Significance

PP3 PM2 PM5

PP4 PM3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.473G>C (p.Arg158Pro) variant in PAH was reported in PMID: 22330942, but was listed as (p.Arg158Gln). Therefore, we are uncertain if the variant is c.473G>C, or p.Arg158Gln. This variant has an extremely low frequency in ExAC and gnomAD (MAF 0.00002). It is predicted deleterious in SIFT, Polyphen2, MutationTaster and REVEL=0.98. Two different pathogenic missense changes at this amino acid have been seen before (R158W, R158Q). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3.

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.98

PM2

Extremely low frequency in ExAC, gnomAD: MAF 0.00002

PM5

R158W and R158Q Pathogenic in ClinVar

PP4

reported as c.473 G>C (p.Arg158Gln) PMID: 22330942

PubMed:22330942

PM3

reported as c.473 G>C (p.Arg158Gln) PMID: 22330942

Approved on: 2020-02-28

Published on: 2020-02-28

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