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_001354304.2:c.684A>C

CA386296575

1065380 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 33ecfb68-253a-4ef9-a345-1da8c398b15d

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_001354304.2:c.684A>C

NC_000012.12:g.102855158T>G

CM000674.2:g.102855158T>G

NC_000012.11:g.103248936T>G

CM000674.1:g.103248936T>G

NC_000012.10:g.101773066T>G

NG_008690.1:g.67445A>C

NG_008690.2:g.108253A>C

ENST00000553106.6:c.684A>C

ENST00000307000.7:c.669A>C

ENST00000549111.5:n.780A>C

ENST00000553106.5:c.684A>C

NM_000277.1:c.684A>C

NM_000277.2:c.684A>C

NM_001354304.1:c.684A>C

NM_000277.3:c.684A>C

Likely Pathogenic

PM3 PP4_Moderate PM2_Supporting PP3

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.684A>C (p.Glu228Asp) variant in PAH is a missense variant in exon 6/13 that is predicted damaging by REVEL (REVEL score 0.688) (PP3_Supporting). It has been previously reported in one individual with PAH deficiency (960μmol/L Phe) with BH4 cofactor deficiency excluded (PMID: 28982351) (PP4_Moderate), who harbored it in trans with the known pathogenic/likely pathogenic variant p.Arg243Gln (ClinVar ID 591) (1pt; PM3_Moderate). A different missense variant at the same site, p.Glu228Lys, is classified as a VUS in ClinVar by the PAH VCEP (ID 120284); thus PM5 is not met. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as Likely Pathogenic based on the ACMG/AMP criteria applied, as specified by the ClinGen Phenylketonuria Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Moderate, PP4_Moderate, PP3_Supporting.

PM3

This variant was detected in trans with the pathogenic PAH variant p.Arg243Gln (path/likely path per multiple submitters, ClinVar ID 591) (1.0pt) PMID: 28982351

PP4_Moderate

This variant was documented 1 time in a patient with PAH deficiency (960μmol/L Phe) in the Han Chinese population (PMID: 28982351), Patients with BH4 cofactor deficiency were excluded

PM2_Supporting

This variant is absent from population databases gnomAD, 1000 Genomes, and ESP.

PP3

REVEL=0.688

PM5

p.Glu228Lys is classified as VUS by PAH VCEP in ClinVar (id 120284)

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