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.694C>G

CA16020842

619160 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 2d2e4a9f-fe71-4d44-a8d9-cc64cd71145d

Approved on: 2018-12-10

Published on: 2018-12-10

HGVS expressions

NM_000277.1:c.694C>G

NC_000012.12:g.102855148G>C

CM000674.2:g.102855148G>C

NC_000012.11:g.103248926G>C

CM000674.1:g.103248926G>C

NC_000012.10:g.101773056G>C

NG_008690.1:g.67455C>G

NG_008690.2:g.108263C>G

NM_000277.2:c.694C>G

NM_001354304.1:c.694C>G

NM_000277.3:c.694C>G

ENST00000307000.7:c.679C>G

ENST00000549111.5:n.790C>G

ENST00000553106.5:c.694C>G

Likely Pathogenic

PS3 PM2

PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.694C>G (p.Gln232Glu) variant in PAH has not been reported in the literature in individuals with PKU. It has been co-expressed with p.E178G and showed 55.0% enzyme activity. PMID: 26803807. BioPKU reports a 42% enzyme activity for this variant (PS3; PMID: 12501224). This variant is absent in population databases (PM2). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2.

PS3

BioPKU: 42% enzyme activity. The co-expression of p.[E178G];[Q232E] showed 55.0% enzyme activity. PMID: 26803807

A dual eukaryotic vector system with two distinct PAH proteins N-terminally fused to different epitope tags was used to investigate the co-expression of PAH alleles reported in patients with inconsistent phenotypes. PAH variant proteins were transiently co-transfected in COS-7 cells. PAH activity was measured by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS), and protein expression was measured by Western blot. The co-expression of p.[E178G];[Q232E] showed 55.0% enzyme activity. PubMed:26803807

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP3

Conflicting predictions

Curation History

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