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.719T>C (p.Phe240Ser)

CA229715

102802 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 40c992e0-e990-4d77-850d-2ded8efbba8f

Approved on: 2020-11-09

Published on: 2022-02-20

HGVS expressions

NM_000277.2(PAH):c.719T>C (p.Phe240Ser)

NM_000277.2:c.719T>C

NC_000012.12:g.102852938A>G

CM000674.2:g.102852938A>G

NC_000012.11:g.103246716A>G

CM000674.1:g.103246716A>G

NC_000012.10:g.101770846A>G

NG_008690.1:g.69665T>C

NG_008690.2:g.110473T>C

ENST00000553106.6:c.719T>C

ENST00000307000.7:c.704T>C

ENST00000549247.6:n.478T>C

ENST00000553106.5:c.719T>C

NM_000277.1:c.719T>C

NM_001354304.1:c.719T>C

NM_000277.3:c.719T>C

NM_001354304.2:c.719T>C

NM_000277.3(PAH):c.719T>C (p.Phe240Ser)

Likely Pathogenic

PP4 PP3 PM2 PM3

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.719T>C (p.Phe240Ser) variant in PAH has been reported in 1 individual with classic PKU detected with pathogenic variant p.R261Q (PMID: 11139255). This variant is absent in population databases. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP3, PP4.

PP4

c.719T>C seen in 1 patient with classic PKU. BH4 deficiency not excluded. PMID: 11139255

These mutations were detected during the characterization of the PAH genotypes of 115 patients with PKU from the southeast region of Brazil. The patients were identified by a neonatal screening program and were considered to have PKU when the phenylalanine levels were above 4 mg/dl. c.719T>C was seen in 1 patient with classic PKU. PubMed:11139255

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.969.

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM3

Detected with R261Q, Path/LP, maternally inherited PMID: 11139255

F240S seen in trans with R261Q (VarID 582, Pathogenic/Likely Pathogenic). IVS2+19T>C polymorphism (VarID 92736, benign) occurred in cis to the F240S mutation, as the mother had these substitutions in the same status. PubMed:11139255

PM5

F240V, no clnical significance provided in ClinVar, US by PAH VCEP

Curation History

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