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

Variant: NM_000277.2(PAH):c.856G>A (p.Glu286Lys)

CA229826

102880 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4dc6bb14-c14b-4cd7-854f-bb6dab99dc54

Approved on: 2018-12-09

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.856G>A

NM_000277.2(PAH):c.856G>A (p.Glu286Lys)

NC_000012.12:g.102851743C>T

CM000674.2:g.102851743C>T

NC_000012.11:g.103245521C>T

CM000674.1:g.103245521C>T

NC_000012.10:g.101769651C>T

NG_008690.1:g.70860G>A

NG_008690.2:g.111668G>A

NM_000277.1:c.856G>A

NM_001354304.1:c.856G>A

NM_000277.3:c.856G>A

ENST00000307000.7:c.841G>A

ENST00000549247.6:n.615G>A

ENST00000551114.2:n.518G>A

ENST00000553106.5:c.856G>A

ENST00000635477.1:n.17G>A

Pathogenic

PP4_Moderate PP3 PM3 PM2 PS3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.856G>A (p.Glu286Lys) variant in PAH is present with low frequency in population databases (1.2e-4), and is predicted to be deleterious using in silico algorithms. It has been identified in trans with pathogenic variants in two independent patients (R243Q, R241C), and has been identified in a patients with Phenylketonuria in which a defect in BH4 metabolism has been excluded (PMID: 14722928, 24401910). Enzyme activity has been measured as 1% of wild type controls (BioPKU). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4_Moderate, PS3, PP3.

PP4_Moderate

BH4 defect excluded in all patients. One patient with classic PKU (Phe=1665umol/L) and one with mild PKU (Phe=610umol/L) (PMID: 14722928). An additional patient with this variant reported with classic PKU (PMID: 24401910)

BH4 defect excluded in all patients. One patient with classic PKU (Phe=1665umol/L) and one with mild PKU (Phe=610umol/L) PubMed:14722928

Single patient with classic PKU PubMed:24401910

PP3

in silico agree on damaging effect REVEL=0.971

PM3

Two independent patients reported, one in trans with R243Q and classic PKU, and one in trans with R241C and mild PKU

Two independent patients reported, one in trans with R243Q and classic PKU, and one in trans with R241C and mild PKU PubMed:14722928

PM2

Allele Frequency: 0.00012

PS3

Enzyme activity 1% per BioPKU

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