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_000277.3(PAH):c.505C>G (p.Arg169Gly)

Curation Version - 1.0
Curation History
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CA16020804

551103 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5391784e-1cfd-43f5-8aba-6f02c44d57b2

Approved on: 2021-02-12

Published on: 2021-02-12

HGVS expressions

NM_000277.3:c.505C>G

NM_000277.3(PAH):c.505C>G (p.Arg169Gly)

NC_000012.12:g.102866600G>C

CM000674.2:g.102866600G>C

NC_000012.11:g.103260378G>C

CM000674.1:g.103260378G>C

NC_000012.10:g.101784508G>C

NG_008690.1:g.56003C>G

NG_008690.2:g.96811C>G

NM_000277.1:c.505C>G

NM_000277.2:c.505C>G

NM_001354304.1:c.505C>G

NM_001354304.2:c.505C>G

ENST00000307000.7:c.490C>G

ENST00000549111.5:n.601C>G

ENST00000551988.5:n.530+10862C>G

ENST00000553106.5:c.505C>G

Pathogenic

PP4_Moderate PM3_Strong PM5 PM2 PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The variant c.505C>G (p.R169G) in PAH has been detected in 2 Chinese patients and 1 Dutch patient with Phe levels >120 umol/l (PMID 26503515, 30050108, 31924462) (PP4-Moderate). This variant was detected in trans with pathogenic variants p.R243Q, p.R241Pfs*100; the validation tests on parents were performed using Sanger sequencing. Also found with pathogenic variant p.Y414C; parental testing not confirmed (PMID: 30050108, 31924462) (PM3-Strong). This variant is absent from controls in gnomAD, 1000 Genomes or ESP (PM2). Multiple lines of computational evidence support a deleterious effect: SIFT, PolyPhen2, and MutationTaster. REVEL score =0.848 (PP4). Missesense variant p.Arg169Ser interpreted as pathogenic by ClinGen PAH VCEP, located at the same amino acid residue (PM5). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4-Moderate, PM3-Strong, PP3, PM5.

PP4_Moderate

R169G is a variant detected in 2 Chinese patients and 1 Dutch patient with Phe levels >120 umol/l (PMID 26503515, 30050108, 31924462). Dihydropteridine reductase activity, urinary biopterin and neopterin ratio and tetrahydrobiopterin loading were collected.

PM3_Strong

This variant was detected in trans with p.R243Q (Pathogenic 11 reports), p.R241Pfs*100 (Likely Pathogenic 2 reports); the validation tests on parents were performed using Sanger sequencing. Found with p.Y414C (Pathogenic 15 reports); parental testing not confirmed (PMID: 30050108, 31924462)

PM5

p.Arg169Ser interpreted as pathogenic by ClinGen PAH VCEP.

PM2

Absent from controls in gnomAD, 1000 Genomes or ESP.

PP3

Multiple lines of computational evidence support a deleterious effect: SIFT, PolyPhen2, and MutationTaster. REVEL score =0.848.

Curation History

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