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_000277.3(PAH):c.280A>G (p.Ile94Val)

CA6748988

883981 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5a2e6217-5f4b-4a08-9226-8d4f319be6a4

HGVS expressions

NM_000277.3:c.280A>G

NM_000277.3(PAH):c.280A>G (p.Ile94Val)

NM_000277.1:c.280A>G

NM_000277.2:c.280A>G

NM_001354304.1:c.280A>G

NM_001354304.2:c.280A>G

ENST00000307000.7:c.265A>G

ENST00000546844.1:c.280A>G

ENST00000548677.2:n.367A>G

ENST00000548928.1:n.202A>G

ENST00000549111.5:n.376A>G

ENST00000550978.6:n.264A>G

ENST00000551337.5:c.280A>G

ENST00000551988.5:n.369A>G

ENST00000553106.5:c.280A>G

NC_000012.12:g.102894807T>C

CM000674.2:g.102894807T>C

NC_000012.11:g.103288585T>C

CM000674.1:g.103288585T>C

NC_000012.10:g.101812715T>C

NG_008690.1:g.27796A>G

NG_008690.2:g.68604A>G

Uncertain Significance

PP4_Moderate

PP3 PM2 PM3 PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.280A>G (p.Ile94Val) variant in PAH was reported in at least three patients with PAH deficiency. BH4 deficiency was ruled out through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay in at least one case (PMID: 30747360, 30459323, and 28982351). This variant is present in the East Asian at a frequency of 0.00160, higher than the PAH Variant Curation Expert Panel cutoff of 0.0002. Computational evidence is conflicting in the predicted effect of this variant. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate.

PP4_Moderate

Three patients were observed, one with mild HPA, one with mild PKU and the other with moderate PKU. 6R-BH4 was ruled out through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay in at least one case. PMID: 30747360, 30459323, and 28982351

PubMed:28982351

PubMed:30459323

PP3

SIFT, PolyPhen2 and MutationTaster disagree on their interpretations of this variant. SIFT predicts tolerated, PolyPhen2 predicts benign, and MutationTaster predicts disease-causing. REVEL=0.554

PM2

Present in East Asian populations at a frequency of 0.00160 and in all populations at a frequency of 0.00011 (gnomAD). Present in East Asian populations at a frequency of 0.00104 and in all populations at a frequency of 0.00007 (ExAC). The PM2 threshold set by the PAH Variant Curation Expert Panel (VCEP) is 0.0002.

PM3

[p.Ile94Val; unknown]. Segregation analysis was done. PMID:28982351

PubMed:30747360

PM5

One other variant in ClinVar is listed as a VUS by a single submitter.

Approved on: 2020-10-15

Published on: 2020-10-15

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