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.185T>C

CA16020739

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: dde01117-4f4b-4e62-bd5c-a3746780d66d

Approved on: 2020-01-29

Published on: 2020-01-31

HGVS expressions

NM_000277.1:c.185T>C

NC_000012.12:g.102894902A>G

CM000674.2:g.102894902A>G

NC_000012.11:g.103288680A>G

CM000674.1:g.103288680A>G

NC_000012.10:g.101812810A>G

NG_008690.1:g.27701T>C

NG_008690.2:g.68509T>C

NM_000277.2:c.185T>C

NM_001354304.1:c.185T>C

NM_000277.3:c.185T>C

ENST00000307000.7:c.170T>C

ENST00000546844.1:c.185T>C

ENST00000548677.2:n.272T>C

ENST00000548928.1:n.107T>C

ENST00000549111.5:n.281T>C

ENST00000550978.6:n.169T>C

ENST00000551337.5:c.185T>C

ENST00000551988.5:n.274T>C

ENST00000553106.5:c.185T>C

ENST00000635500.1:n.153T>C

Likely Pathogenic

PM3 PM2 PP3 PP4

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.185T>C (p.Leu62Pro) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency not assessed/reported). (PP4; PMID: 22513348). This variant is absent in population databases (PM2). This variant was detected with p.R408W (Pathogenic in ClinVar) (PM3; PMID: 22513348). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3, PP3.

PM3

Detected with R408W (pathogenic in ClinVar) PMID: 22513348

Patient 38: allele 1:p.L62P, allele 2: R408W. PubMed:22513348

PM2

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

PP3

Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster). REVEL=0.972

PP4

Novel mutation detected in a patient with classic PKU: p.L62P. BH4 deficiencies not assessed/reported. PMID: 22513348

Mutational spectrum of PAH deficiency was investigated in 107 families (90% of the Slovene PKU population). The entire coding region of the PAH gene was analyzed with dHPLC to select the samples where subsequently the automated sequencing analysis was performed. MLPA analysis was performed to identify large deletions, which were later confirmed with long-range PCR. Novel mutation detected in a patient with classic PKU: p.L62P. PubMed:22513348

Curation History

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