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.1112A>G (p.Lys371Arg)

CA229348

102527 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 25c4af2f-d04a-4400-ad30-4d12c850bf10

Approved on: 2021-04-23

Published on: 2021-05-14

HGVS expressions

NM_000277.3:c.1112A>G

NM_000277.3(PAH):c.1112A>G (p.Lys371Arg)

ENST00000553106.6:c.1112A>G

ENST00000307000.7:c.1097A>G

ENST00000549247.6:n.871A>G

ENST00000551114.2:n.774A>G

ENST00000553106.5:c.1112A>G

ENST00000635477.1:n.216A>G

ENST00000635528.1:n.627A>G

NM_000277.1:c.1112A>G

NM_000277.2:c.1112A>G

NM_001354304.1:c.1112A>G

NM_001354304.2:c.1112A>G

NC_000012.12:g.102843733T>C

CM000674.2:g.102843733T>C

NC_000012.11:g.103237511T>C

CM000674.1:g.103237511T>C

NC_000012.10:g.101761641T>C

NG_008690.1:g.78870A>G

NG_008690.2:g.119678A>G

Uncertain Significance

PM3_Supporting PP4_Moderate PM2

PP3 PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1112A>G (p.Lys371Arg) variant in PAH has been reported in a patient with PKU (BH4 deficiency excluded) (PMID: 23430918, 9169088) detected with pathogenic variant IVS10-11G>A, parental analysis not reported PMID: 9169088. This variant is absent in population databases. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_moderate, PM2, PP3_supporting.

PM3_Supporting

Reported with IVS10-11G>A, parental analysis not reported PMID: 9169088 (0.5)

PP4_Moderate

Detected in a patient with PKU (Phe 806) Clinical diagnosis of primary BH4 deficiency was excluded (Ok to upgrade to Moderate since Sarkissian is a Clinical trial) PMID: 23430918, PMID: 9169088

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PP3

Computational evidence is conflicting: Tolerated in SIFT, PolyPhen2, REVEL=0.658; Disease causing in MutationTaster

PM5

The current variant is the only variant found in this codon in ClinVar.

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