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.842+3G>C

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CA229814

102871 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ad7649c8-a5c0-4598-8404-91fbd76346b9

Approved on: 2018-09-11

Published on: 2019-04-06

HGVS expressions

NM_000277.2:c.842+3G>C

NM_000277.2(PAH):c.842+3G>C

NC_000012.12:g.102852812C>G

CM000674.2:g.102852812C>G

NC_000012.11:g.103246590C>G

CM000674.1:g.103246590C>G

NC_000012.10:g.101770720C>G

NG_008690.1:g.69791G>C

NG_008690.2:g.110599G>C

NM_000277.1:c.842+3G>C

NM_001354304.1:c.842+3G>C

NM_000277.3:c.842+3G>C

ENST00000307000.7:c.827+3G>C

ENST00000549247.6:n.601+3G>C

ENST00000553106.5:c.842+3G>C

ENST00000635477.1:n.3+3G>C

Likely Pathogenic

PM3_Strong PP4_Moderate PM2

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in gnomAD+ExAC (MAF=0.00006). Absent from 1000G, ESP.; PP4_Moderate: Detected in Costa Rican and 1 Spanish PKU patients, exclusion of defects in tetrahydrobiopterine metabolism. (PMID:8860005; PMID:8981952); PM3_Strong: Detected in trans with I269L and R408W, known pathogenic variants. (PMID:9521426; PMID:23430918). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong).

PM3_Strong

Detected in trans with I269L and R408W, known pathogenic variants.

Patient F100: c.842+3g→c (IVS7nt3)/c.805A→C (I269L) (VarID 102842, Pathogenic). PubMed:9521426

Genotype: c.842+3G>C: p.R408W (VarID 577, Pathogenic) PubMed:23430918

PP4_Moderate

Detected in Costa Rican and 1 Spanish PKU patients, exclusion of defects in tetrahydrobiopterine metabolism.

Detected on 4 Costa Rican classical PKU alleles. (IVS7nt3) PubMed:8860005

Detected in 1 Spanish PKU patient. Patients were considered as having PKU when the serum phenylalanine levels at diagnosis were >600 umol/liter and after exclusion of a defect in tetrahydrobiopterine metabolism. PubMed:8981952

PM2

Extremely low frequency in gnomAD+ExAC (MAF=0.00006). Absent from 1000G, ESP.

Curation History

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