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.820A>G (p.Lys274Glu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229786

102851 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f459ef35-b6d1-4155-b1aa-7bb752fd55a0

Approved on: 2018-08-10

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.820A>G

NM_000277.2(PAH):c.820A>G (p.Lys274Glu)

NC_000012.12:g.102852837T>C

CM000674.2:g.102852837T>C

NC_000012.11:g.103246615T>C

CM000674.1:g.103246615T>C

NC_000012.10:g.101770745T>C

NG_008690.1:g.69766A>G

NG_008690.2:g.110574A>G

NM_000277.1:c.820A>G

NM_001354304.1:c.820A>G

NM_000277.3:c.820A>G

ENST00000307000.7:c.805A>G

ENST00000549247.6:n.579A>G

ENST00000553106.5:c.820A>G

Likely Benign

BS3_Supporting BS1

PM5 PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: BS1: MAF= 0.01815 in 1000G. 2 homozygotes in ExAC, 1 homozygote in 1000G.; BS3_Supporting: Enzyme activity of K274E is indistinguishable from that of the wild-type protein. Detailed kinetic analyses of PAH expressed in E. coli showed that the K274E mutant protein has kinetic properties similar to that of the wild-type protein. (PMID:11461196). In summary this variant meets criteria to be classified as likely benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BS3_Supporting).

BS3_Supporting

Enzyme activity of K274E is indistinguishable from that of the wild-type protein. Detailed kinetic analyses of PAH expressed in E. coli showed that the K274E mutant protein has kinetic properties similar to that of the wild-type protein.

Expression analyses in two different in vitro systems showed that I318T is associated with profoundly decreased enzyme activity, whereas the enzyme activity of K274E is indistinguishable from that of the wild-type protein. Detailed kinetic analyses of PAH expressed in E. coli showed that the K274E mutant protein has kinetic properties similar to that of the wild-type protein. PubMed:11461196

BS1

MAF= 0.01815 in 1000G. 2 homozygotes in ExAC, 1 homozygote in 1000G.

PM5

this is the only variant in this codon in ClinVar

PP3

Conflicting predictions: tolerated and benign in SIFT/Polyphen2, disease causing in MutationTaster. REVEL=0.513

Curation History

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