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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CA16020734

555212 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 7cb3c9a2-47a2-4ec3-8c6e-7ab64592450a

HGVS expressions

NC_000012.12:g.102894920T>C

CM000674.2:g.102894920T>C

NC_000012.11:g.103288698T>C

CM000674.1:g.103288698T>C

NC_000012.10:g.101812828T>C

NG_008690.1:g.27683A>G

NG_008690.2:g.68491A>G

NM_000277.1:c.169-2A>G

NM_000277.2:c.169-2A>G

NM_001354304.1:c.169-2A>G

NM_000277.3:c.169-2A>G

ENST00000307000.7:c.154-2A>G

ENST00000546844.1:c.169-2A>G

ENST00000548677.2:n.256-2A>G

ENST00000548928.1:n.91-2A>G

ENST00000549111.5:n.265-2A>G

ENST00000550978.6:n.153-2A>G

ENST00000551337.5:c.169-2A>G

ENST00000551988.5:n.258-2A>G

ENST00000553106.5:c.169-2A>G

ENST00000635500.1:n.137-2A>G

Pathogenic

PVS1 PP4 PM2 PM3 PP1_Moderate

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.169-2A>G variant has been identified in at least 1 proband with classic PKU (PMID: 24368688). It has been detected in the homozygous form (PMID: 20188615) as well as in trans with the pathogenic variant Gly272Ter (PMID: 24368688). This variant is present at very low allele frequencies; 0.000007993 overall in gnomAD with a MAF of 0.00003267 (1/30612) in the South Asian population. Computational analysis predicts an alteration of the WT acceptor site, most probably affecting splicing, generating a frameshift, and leading to nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM3, PM2, PP1_Moderate, PP4.

PVS1

This variant breaks the -2 splice site in IVS2 according to MaxEntScan (-67.49% variation) and HSF (-33.18% variation) and generates a nearby upstream cryptic splice site. This would result in a frameshift generating a stop codon two residues downstream and is predicted to lead to NMD.

PP4

At least one homozygous patient has classic PKU with Phe >1200 μmol/L.

PM2

This variant is found at an extremely low allele frequency of 0.000007993 overall in gnomAD with a MAF of 0.00003267 (1/30612) in the South Asian population.

PM3

One homozygous proband and one compound heterozygote has been reported for this c.169-2A>G with ClinVar 596 pathogenic variant c.814G>T (p.G272Ter).

PP1_Moderate

One family has been reported with three affected individuals, homozygous for this variant.

Approved on: 2019-08-26

Published on: 2019-08-26

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