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.559T>C (p.Trp187Arg)

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CA229622

102735 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c4c72f19-332b-48fb-b8ef-beaa7c0646fb

Approved on: 2018-12-11

Published on: 2019-05-04

HGVS expressions

NM_000277.2:c.559T>C

NM_000277.2(PAH):c.559T>C (p.Trp187Arg)

NC_000012.12:g.102855283A>G

CM000674.2:g.102855283A>G

NC_000012.11:g.103249061A>G

CM000674.1:g.103249061A>G

NC_000012.10:g.101773191A>G

NG_008690.1:g.67320T>C

NG_008690.2:g.108128T>C

NM_000277.1:c.559T>C

NM_001354304.1:c.559T>C

NM_000277.3:c.559T>C

ENST00000307000.7:c.544T>C

ENST00000549111.5:n.655T>C

ENST00000551988.5:n.580T>C

ENST00000553106.5:c.559T>C

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3_Strong

BP4 BA1 BS1

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The PAH: c.559T>C (p.Trp187Arg) variant was found in two cases in trans with other P/LP alleles: one case with classic PKU (assessed via plasma Phe measurement in trans with the p.R158Q allele (PMID: 18956252) and one case whose PKU sub-phenotype was not mentioned in trans with the p.R261Q allele (PMID: 23074961) (PM3_Strong). It has also been found in trans with the p.Gln419Arg allele, classified as Likely Pathogenic in ClinVar, in 1 case with mild hyperphenylalanemia (BH4 deficiency excluded. PP4_moderate. PMID: 28982351). The variant is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is predicted damaging by multiple lines of computational evidence: SIFT, Polyphen2, Mutation Taster, REVEL = 0.918 (PP3). 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

Found in at least 1 case with classic PKU (PMID: 18956252). Reported in a patient with mild hyperphenylalaninemia (250 umol/L). BH4 cofactor deficiency excluded. PMID: 28982351

A total of 655 unrelated Han families, in which at least one member was diagnosed with PKU, were recruited at the genetic counseling clinic of the First Affiliated Hospital of Zhengzhou University, the neonatal screening center of the Third Affiliated Hospital of Zhengzhou University, or Zhengzhou Maternity and Child Care Hospital between January 2008 and January 2016. Patients with BH4 cofactor deficiency were excluded. Patient 488: p.Trp187Arg/p.Gln419Arg, 240, mHP. PubMed:28982351

RAMEDIS ID 533: Allele 1: p.R158Q, Allele 2: p.W187R PubMed:18956252

PP3

It is predicted damaging by multiple lines of computational evidence: SIFT, Polyphen2-HumDiv and Polyphen2-HumVar, Mutation Taster, REVEL = 0.918 (PP3).

PM2

The variant is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).

PM3_Strong

It was found in two cases in trans with other P/LP alleles: one case with classic PKU (assessed via plasma Phe measurement in trans with the p.R158Q allele (PMID: 18956252) (PP4) and one case whose PKU sub-phenotype was not mentioned in trans with the p.R261Q allele (PMID: 23074961) (PM3_Strong). It has also been found in trans with the p.Gln419Arg, classified as Likely Pathogenic in ClinVar, in 1 case with mild hyperphenylalanemia (PMID 28982351).

found in 1 case, in trans with p.R261Q (established pathogenic allele); phenotype not mentioned PubMed:23074961

found in trans with p.Gln419Arg (classified LP by Counsyl in ClinVar) allele in 1 case with mild hyperphenylalanemia PubMed:28982351

found in 1 case, in trans with p.R158Q allele (established pathogenic allele). Patient was German male diagnosed at 5d old with classic PKU based on plasma Phe, BH4 deficiency does not appear to have been excluded (see https://agbi.techfak.uni-bielefeld.de/ramedis/htdocs/dm-guest/case_main.php?patID=533). PubMed:18956252

BP4

It is predicted damaging by multiple lines of computational evidence: SIFT, Polyphen2-HumDiv and Polyphen2-HumVar, Mutation Taster, REVEL = 0.918 (PP3).

BA1

The variant is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).

BS1

The variant is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).

Curation History

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