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(PAH):c.922C>G (p.Leu308Val)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229849

102895 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 220a2761-ff28-4e58-a382-7a56bab8d9dd

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000277.1:c.922C>G

NM_000277.1(PAH):c.922C>G (p.Leu308Val)

NC_000012.12:g.102846942G>C

CM000674.2:g.102846942G>C

NC_000012.11:g.103240720G>C

CM000674.1:g.103240720G>C

NC_000012.10:g.101764850G>C

NG_008690.1:g.75661C>G

NG_008690.2:g.116469C>G

ENST00000553106.6:c.922C>G

ENST00000307000.7:c.907C>G

ENST00000549247.6:n.681C>G

ENST00000551114.2:n.584C>G

ENST00000553106.5:c.922C>G

ENST00000635477.1:c.74-2511C>G

ENST00000635528.1:n.437C>G

NM_000277.2:c.922C>G

NM_001354304.1:c.922C>G

NM_000277.3:c.922C>G

NM_001354304.2:c.922C>G

Likely Pathogenic

PP3_Moderate PS3_Supporting PM3 PP4 PM2_Supporting

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.1(PAH):c.922C>G (p.Leu308Val) variant is a missense variant in exon 9/13 of PAH. The variant has been found to reduce PAH enzymatic activity to 15-19% versus wild type PAH enzyme in transfected COS cells (PMID: 18590700). The variant has been previously reported in confirmed trans with the c.1315+1G>A variant (Pathogenic per ClinGen PAH VCEP) in a patient with mild PKU (plasma Phe 600-900 umol/L); BH4 deficiency does not appear to have been excluded (PMID: 26542770). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP. The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.892). Classification: Likely Pathogenic Supporting Criteria: PS3_supporting; PM2_supporting; PM3; PP4; PP3_moderate

PP3_Moderate

All databases agree on damaging effect. REVEL = 0.892

PS3_Supporting

Enzyme activity = 19% (PMID: 18590700)

PAH activity analysis. Site directed mutagenesis, transfected COS-1 cells. Enzyme activity measured as conversion of L-[14C]phe to L-[14C]tyr. Use both standard cDNA expression system and a new Intinic plasmid system which incorporates intronic sequences. Standard cDNA method demonstrates 15% and intinic system demonstrates 19% residual enzyme activity. PubMed:18590700

PM3

Single patient c.1315+1G>A (pathogenic in ClinVar) / c.922C>G with mild PKU

376 patients in Denmark, represents all patients diagnosed with PKU between 1967-2014. PubMed:26542770

PP4

Single patient with mild PKU (values 600-900). No specific level provided.

PM2_Supporting

not found in gnomAD v2.1.1

Curation History

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