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_000277.1(PAH):c.926C>T (p.Ala309Val)

CA220592

92753 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: db2881e3-3790-4e61-95e9-4ee16b4291d4

HGVS expressions

NM_000277.1:c.926C>T

NM_000277.1(PAH):c.926C>T (p.Ala309Val)

NC_000012.12:g.102846938G>A

CM000674.2:g.102846938G>A

NC_000012.11:g.103240716G>A

CM000674.1:g.103240716G>A

NC_000012.10:g.101764846G>A

NG_008690.1:g.75665C>T

NG_008690.2:g.116473C>T

NM_000277.2:c.926C>T

NM_001354304.1:c.926C>T

NM_000277.3:c.926C>T

ENST00000307000.7:c.911C>T

ENST00000549247.6:n.685C>T

ENST00000551114.2:n.588C>T

ENST00000553106.5:c.926C>T

ENST00000635477.1:n.74-2507C>T

ENST00000635528.1:n.441C>T

Pathogenic

PS3 PM3 PM2 PP3 PP4

Evidence Links 2

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: PM2: Low frequency. 1.0e-5; PP3: All databases agree on damaging effect. REVEL=0.921; PS3: Enzyme activity = 30% (Ho, 2008) (PMID:18590700); PM3: Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T (PMID:26666653); PP4: Single patient with classic PKU (>1200umol/L), BH4 defect not excluded (PMID:26666653). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4).

PS3

Enzyme activity = 30% (Ho, 2008)

PAH activity analysis. Site directed mutagenesis, transfected COS-1 cells. Enzyme activity measured as conversion of L-[14C]phe to L-[14C]tyr. Use both standard cDNA expression system and a new Intinic plasmid system which incorporates intronic sequences. Standard cDNA method demonstrates 30% and intinic system demonstrates 14% residual enzyme activity. PubMed:18590700

PM3

Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T

Genotype-phenotype association in French patients with PKU. 364 patients, 24hr BH4 loading test. PubMed:26666653

PM2

Low frequency. 1.0e-5

PP3

All databases agree on damaging effect. REVEL=0.921

PP4

Single patient with classic PKU (>1200umol/L), BH4 defect not excluded

Genotype-phenotype association in French patients with PKU. 364 patients, 24hr BH4 loading test. PubMed:26666653

Approved on: 2018-08-10

Published on: 2019-04-05

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