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]

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Variant: NM_000277.2(PAH):c.791A>T (p.His264Leu)

CA229761

102834 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e218babf-baa5-4179-a104-b0252fef5c9c

HGVS expressions

NM_000277.2:c.791A>T

NM_000277.2(PAH):c.791A>T (p.His264Leu)

NC_000012.12:g.102852866T>A

CM000674.2:g.102852866T>A

NC_000012.11:g.103246644T>A

CM000674.1:g.103246644T>A

NC_000012.10:g.101770774T>A

NG_008690.1:g.69737A>T

NG_008690.2:g.110545A>T

NM_000277.1:c.791A>T

NM_001354304.1:c.791A>T

NM_000277.3:c.791A>T

NM_001354304.2:c.791A>T

ENST00000307000.7:c.776A>T

ENST00000549247.6:n.550A>T

ENST00000553106.5:c.791A>T

Uncertain Significance

PP3 PM1 PM2

PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.791A>T (p.His264Leu) variant in PAH has not been reported in the literature, to our knowledge. References in BioPKU/PAHdb (Cardoso 2001) cannot be located. This variant is absent from ExAC, GnomAD, 1000G, and ESP. It is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.949. The H264 residue interacts directly with the BH4 cofactor. (PMID: 12126628). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM1, PM2, PP3.

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.949

PM1

The H264 residue interacts directly with a BH4 analogue. PMID: 12126628

Table 2. Amino acid residues in the active-site crevice structure involved in the binding of pterin cofactor and substrate and missense single-point mutations that have been reported in these residues in human hyperphenylalaninemias. BH4: His264. Binds BH4 only in the binary complex via a water bridge. PubMed:12126628

The R261Q mutation detected in patient 2 lies very close to one of the residues (H264) shown to interact directly with a BH4 analogue in the phenylalanine crystal structure (Erlandsen et al 2000) and it is conceivable that this and other mutations will alter the tertiary structure of the catalytic domain. This may change the affinity of phenylalanine hydroxylase for its cofactor, resulting in a higher Km for BH4. PubMed:11999982

PM2

Absent from ExAC, GnomAD, 1000G, ESP

PM5

This is the only variant found in this codon in ClinVar.

Approved on: 2018-12-10

Published on: 2019-04-05

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