The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

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

CA229826

102880 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
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
More

Pathogenic

Met criteria codes 5
PS3 PP4_Moderate PP3 PM2 PM3

Evidence Links 2

Expert Panel

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.
Met criteria codes
PS3
Enzyme activity 1% per BioPKU
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)

PP3
in silico agree on damaging effect REVEL=0.971
PM2
Allele Frequency: 0.00012
PM3
Two independent patients reported, one in trans with R243Q and classic PKU, and one in trans with R241C and mild PKU

Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.