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_000277.1(PAH):c.913-7A>G

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Curation History
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CA229848

102894 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b4ecce45-4b5e-464f-be37-d7949b576c34

Approved on: 2020-02-16

Published on: 2020-02-16

HGVS expressions

NM_000277.1:c.913-7A>G

NM_000277.1(PAH):c.913-7A>G

NM_000277.2:c.913-7A>G

NM_001354304.1:c.913-7A>G

NM_000277.3:c.913-7A>G

NM_001354304.2:c.913-7A>G

ENST00000307000.7:c.898-7A>G

ENST00000549247.6:n.672-7A>G

ENST00000551114.2:n.575-7A>G

ENST00000553106.5:c.913-7A>G

ENST00000635477.1:n.74-2527A>G

ENST00000635528.1:n.421A>G

NC_000012.12:g.102846958T>C

CM000674.2:g.102846958T>C

NC_000012.11:g.103240736T>C

CM000674.1:g.103240736T>C

NC_000012.10:g.101764866T>C

NG_008690.1:g.75645A>G

NG_008690.2:g.116453A>G

Likely Pathogenic

PP4_Moderate PM2 PP3 PM3_Strong

Evidence Links 10

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.913-7A>G variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded) PMID: 9634518, 16601866. This variant has extremely low frequency in gnomAD (MAF=0.00003). This variant was detected with 10 different variants for a total of 3.75 points (PM3_Strong. Computational evidence predicts splicing changes. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_Strong, PP3.

PP4_Moderate

PMID 9634518 lists it as a classic PKU variant. PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism. PMID: 16601866 identified with mild PKU. A defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes.

PubMed:16601866

PMID 9634518 lists it as a classic PKU variant. Quote "In all patients, hyperphenylalaninemia had been detected by national mass screening programs, and PAH deficiency had been assessed after exclusion of a defect in tetrahydrobiopterin metabolism." PubMed:9634518

PMID 8981952: identified in this cohort of patients (Phe level not specified for this variant) PubMed:8981952

PM2

Extremely low frequency in gnomAD MAF=0.00003

PP3

Splicing predictions at nearest natural junction:Predicted change at acceptor site 7 bps downstream: -17.4%, MaxEnt: -62.2%, NNSPLICE: 9.9%, HSF: -0.1%. But it seems to create a new splice acceptor site. ©Interactive Biosoftware - Created by Alamut Visual v.2.9.0 on 5/15/2017

PM3_Strong

Detected in trans with R261Q (P, 9 submitters) PMID: 16601866 confirmed by analysing parental DNA. Detected with p.N133Rfs (not in ClinVar). Detected with R408W (P, 14 submitters) PMID: 24350308 parental analysis not reported. Detected with IVS9+5G>A (no assertion in ClinVar) PMID: 24048906. Detected in trans with p.G312R (VUS) confirmed on parental DNA PMID: 24130151 Detected with R241C (P, 7 submitters) and G312V (not in ClinVar) parental analysis not confirmed PMID: 24401910 Detected with p.Arg243Gln (P, 9 submitters) and p.Arg261Gly (LP) parental analysis not reported PMID: 26666653 Total of 3.75 pts

PubMed:24401910

PubMed:24350308

PubMed:22513348

PubMed:26666653

PubMed:26322415

PubMed:24130151

PubMed:24048906

Curation History

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