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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001354304.2:c.920G>A

CA16020898

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e2f311ba-7dbb-425f-baa6-56501a3faf9c

HGVS expressions

NM_001354304.2:c.920G>A

NC_000012.12:g.102846944C>T

CM000674.2:g.102846944C>T

NC_000012.11:g.103240722C>T

CM000674.1:g.103240722C>T

NC_000012.10:g.101764852C>T

NG_008690.1:g.75659G>A

NG_008690.2:g.116467G>A

ENST00000553106.6:c.920G>A

ENST00000307000.7:c.905G>A

ENST00000549247.6:n.679G>A

ENST00000551114.2:n.582G>A

ENST00000553106.5:c.920G>A

ENST00000635477.1:n.74-2513G>A

ENST00000635528.1:n.435G>A

NM_000277.1:c.920G>A

NM_000277.2:c.920G>A

NM_001354304.1:c.920G>A

NM_000277.3:c.920G>A

Likely Pathogenic

PM2 PP4_Moderate PM3_Strong PP3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The NM_000277.3:c.920G>A (p.Gly307Asp) variant is a missense variant in exon 9/13 of PAH. The variant has been reported in confirmed trans with the p.R111* variant (Pathogenic per ClinGen PAH VCEP) in a Chinese patient with mild PKU (plasma Phe 10–20 mg/dl); BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PMID: 26322415) (PP4_Moderate). It has also been found in presumed trans in 2 Polish cases: one patient with genotype F55Lfs/G307D with mild PKU and one patient with genotype R408W/G307D with unspecified Phe levels (PMID: 24350308) (PM3_Strong, 2 points total). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant is predicted damaging by multiple in-silico missense predictors, including REVEL (REVEL score 0.983) (PP3). Classification: Likely Pathogenic Supporting Criteria: PM3; PM2; PP4_Moderate; PP3

PM2

Not found in any population database

PP4_Moderate

BH4 defects excluded in all patients. Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU

BH4 defects excluded in all patients. Single patient in this paper c.920G>A/C.331C>T (pathogenic) with mild PKU PubMed:26322415

PM3_Strong

one patient F55Lfs/G307D with mild PKU and one patient R408W/G307D with unspecified Phe levels (PMID: 24350308). Also found in one patient with mild PKU and genotype R111*/G307D (PMID: 26322415)

2 patients with c.920G>A in trans with pathogenic variants PubMed:24350308

PP3

All computational evidence suggests damaging variant. REVEL=0.983

Approved on: 2022-06-12

Published on: 2022-06-12

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