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_000277.2(PAH):c.3G>C (p.Met1Ile)

Curation Version - 1.0
Curation History
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CA386303909

585206 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 163d78d0-7557-412d-9bdf-155b6085537a

Approved on: 2019-07-07

Published on: 2019-07-07

HGVS expressions

NM_000277.2:c.3G>C

NM_000277.2(PAH):c.3G>C (p.Met1Ile)

NC_000012.12:g.102917128C>G

CM000674.2:g.102917128C>G

NC_000012.11:g.103310906C>G

CM000674.1:g.103310906C>G

NC_000012.10:g.101835036C>G

NG_008690.1:g.5475G>C

NG_008690.2:g.46283G>C

NM_000277.1:c.3G>C

NM_001354304.1:c.3G>C

NM_000277.3:c.3G>C

ENST00000307000.7:c.-145G>C

ENST00000546844.1:c.3G>C

ENST00000547319.1:n.314G>C

ENST00000549111.5:n.99G>C

ENST00000551337.5:c.3G>C

ENST00000551988.5:n.92G>C

ENST00000553106.5:c.3G>C

ENST00000635500.1:n.29-4230G>C

Likely Pathogenic

PM2 PVS1

PS1 PP4 PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.3G>C (p.Met1Ile) variant in PAH is a null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. This variant is absent in population databases (PM2). This variant has not been reported in an affected individual in the literature to our knowledge. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PVS1.

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PVS1

Null variant (start loss) where LOF is a known mechanism of disease. There are no known alternative start codons in other transcripts. The next in-frame Met is at amino acid 180 in exon 6. There are 49 pathogenic variants in ClinVar upstream of aa 180. The p.Met1Val variant has <3% enzyme activity as compared to wild type (PMID: 9450897), confirming start loss variants lead to loss of function of the PAH enzyme without re-initiation. Kept at full strength per Steven Harrison.

PS1

Loss of function start loss variant

PP4

Not reported in the literature

PM5

Loss of function start loss variant

Curation History

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