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

CA16020911

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0f0241f8-e9df-4a3c-988b-27c81a170109

HGVS expressions

NM_000277.1:c.970A>G

NM_000277.2:c.970A>G

NM_001354304.1:c.970A>G

NM_000277.3:c.970A>G

NM_001354304.2:c.970A>G

ENST00000307000.7:c.955A>G

ENST00000549247.6:n.729A>G

ENST00000551114.2:n.632A>G

ENST00000553106.5:c.970A>G

ENST00000635477.1:n.74A>G

ENST00000635528.1:n.485A>G

NC_000012.12:g.102844431T>C

CM000674.2:g.102844431T>C

NC_000012.11:g.103238209T>C

CM000674.1:g.103238209T>C

NC_000012.10:g.101762339T>C

NG_008690.1:g.78172A>G

NG_008690.2:g.118980A>G

Uncertain Significance

PM2 PM3 PP4

PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3:c.970A>G (p.Ile324Val) variant is a missense variant in exon 10/13 of PAH. It has been previously reported in a patient with mild hyperphenylalanemia (plasma Phe 230 uM) in confirmed trans with the c.441+5G>T variant (ClinVar Pathogenic (ID 92742); Pathogenic per ClinGen PAH VCEP); BH4 deficiency was not stated to have been excluded (PP4; PM3) (PMID: 15159646). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In-silico pathogenicity predictors are conflicting and REVEL=0.534, such that PP3 is not met. Classification: VUS – insufficient evidence Supporting Criteria: PM2; PM3; PP4

PM2

Variant not found in any pop database

PM3

c.[(970A>G)];[(441+5G>T)] (pathogenic in clinvar)

Single patient c.[(970A>G)];[(441+5G>T)] (pathogenic in clinvar). Phase determined via parental studies PubMed:15159646

PP4

Phe 230umol/L at initial screening and 180umol/L with no dietary restriction.

c.[(970A>G)];[(441+5G>T)] single patient PubMed:15159646

PP3

in silico predictors do not agree. REVEL=0.534

Approved on: 2020-07-25

Published on: 2020-07-25

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