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_000277.1:c.859C>G

CA6748814

619164 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 381aa0a0-283a-47df-a1b8-0180f05e3d16

Approved on: 2018-12-09

Published on: 2018-12-10

HGVS expressions

NM_000277.1:c.859C>G

NC_000012.12:g.102851740G>C

CM000674.2:g.102851740G>C

NC_000012.11:g.103245518G>C

CM000674.1:g.103245518G>C

NC_000012.10:g.101769648G>C

NG_008690.1:g.70863C>G

NG_008690.2:g.111671C>G

NM_000277.2:c.859C>G

NM_001354304.1:c.859C>G

NM_000277.3:c.859C>G

ENST00000307000.7:c.844C>G

ENST00000549247.6:n.618C>G

ENST00000551114.2:n.521C>G

ENST00000553106.5:c.859C>G

ENST00000635477.1:n.20C>G

Likely Pathogenic

PM2 PP4_Moderate PM3_Strong

PP3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.859C>G (p.Leu287Val) variant in PAH is found with low allele frequency in population databases (3.0e-5). It has been identified in trans with pathogenic variants in two individuals in the literature (P281L and A300S, PMID: 12409276), and in one of those patients a defect in BH4 metabolism was excluded as a cause of elevated phenylalanine (PMID: 16198137). . In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3.

PM2

Allele Frequency: 0.00003

PP4_Moderate

BH4 defect excluded in all patients (Fiori) PMID: 16198137

BH4 defect excluded in all patients, single patient with mild Hyperphe (Phe=167.40umol/L) PubMed:16198137

PM3_Strong

281L (Pathogenic)( PMID: 12409276), and A300S (pathogenic)(PMID: 16198137)

Single patient in trans with P281L, classic PKU PubMed:12409276

Single patient with MHP, in trans with A300S PubMed:16198137

PP3

Provean=neutral, SIFT=damaging. REVEL=0.822

Curation History

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