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_000277.3(PAH):c.510-6T>G

CA229596

102714 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c1826d9c-ad78-4e87-aa15-ac000ee420ee

HGVS expressions

NM_000277.3:c.510-6T>G

NM_000277.3(PAH):c.510-6T>G

NM_000277.1:c.510-6T>G

NM_000277.2:c.510-6T>G

NM_001354304.1:c.510-6T>G

NM_001354304.2:c.510-6T>G

ENST00000307000.7:c.495-6T>G

ENST00000549111.5:n.606-6T>G

ENST00000551988.5:n.531-6T>G

ENST00000553106.5:c.510-6T>G

NC_000012.12:g.102855338A>C

CM000674.2:g.102855338A>C

NC_000012.11:g.103249116A>C

CM000674.1:g.103249116A>C

NC_000012.10:g.101773246A>C

NG_008690.1:g.67265T>G

NG_008690.2:g.108073T>G

Uncertain Significance

PP4 PM2 PM3_Supporting

BP7

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.510-6T>G variant in PAH is absent from population databases (PM2). It has been observed in at least one classic PKU patient (PMID: 23764561; PP4). The patient is compound heterozygous with pathogenic variant R408W (ClinVar 577; PM3_supporting). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP4.

PP4

Patient 51 of PMID: 23764561 has classic PKU with Phe ≥ 1200 μmol/L. Authors state that patients with BH4 deficiency were excluded but do not say by what method BH4 deficiency was excluded.

PM2

The c.510-6T>G variant is absent from population databases including gnomAD, ExAC, 1000 Genomes, and ESP.

PM3_Supporting

Patient 51 of PMID: 23764561 is compound heterozygous for c.510-6T>G and R408W (ClinVar 577 Pathogenic, reviewed by PAH VCEP). Confirmation of trans phase not reported.

BP7

HSF and MaxEntScan predict no significant impact on splicing signals, however the nucleotide is highly conserved across vertebrates (PhyloP score of 6.66).

Approved on: 2020-09-12

Published on: 2020-09-12

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