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_000277.1(PAH):c.722G>A (p.Arg241His)

Curation Version - 1.0
Curation History
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CA286507

102804 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 86e24192-6435-4be3-a366-79ac5a804969

Approved on: 2018-08-10

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.722G>A

NM_000277.1(PAH):c.722G>A (p.Arg241His)

NC_000012.12:g.102852935C>T

CM000674.2:g.102852935C>T

NC_000012.11:g.103246713C>T

CM000674.1:g.103246713C>T

NC_000012.10:g.101770843C>T

NG_008690.1:g.69668G>A

NG_008690.2:g.110476G>A

NM_000277.2:c.722G>A

NM_001354304.1:c.722G>A

NM_000277.3:c.722G>A

ENST00000307000.7:c.707G>A

ENST00000549247.6:n.481G>A

ENST00000553106.5:c.722G>A

Pathogenic

PP4_Moderate PP3 PM2 PM5 PM3_Strong

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC, gnomAD, 1000G, ESP (0.000077- 0.0001518); PP3: Predicted deleterious in SIFT, PolyPhen2, MutationTaster; PM5: R241C (VarID 102803) is Pathogenic in ClinVar based on 3 submitters; PP4_Moderate: R241H seen in 1 PKU patient. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_Strong: R241H detected in trans with pathogenic variants (IVS10, R408W, R252W). Upgraded per ClinGen SVI Workgroup. (PMID:9429153). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PM5, PP4_Moderate, PM3_Strong).

PP4_Moderate

R241H seen in 1 PKU patient. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG.

Subjects included 53 unrelated patients. All patients with blood phenylalanine levels persistently above 150 umol/l. The criteria for inclusion were: normal serum tyrosine, normal urinary excresion of biopterin and neopterin, and no indication of acquired hyperphenylalaninemia. R241H was seen on 1 allele. PubMed:8268925

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster

PM2

Extremely low frequency in ExAC, gnomAD, 1000G, ESP (0.000077- 0.0001518)

PM5

R241C (VarID 102803) is Pathogenic in ClinVar based on 3 submitters

PM3_Strong

R241H detected in trans with pathogenic variants (IVS10, R408W, R252W). Upgraded per ClinGen SVI Workgroup.

R241H found in 3 patient with mild PKU, in trans with R252W (VarID 584, Pathogenic/Likely Pathogenic in ClinVar), IVS1O (VarID 607, Pathogenic in ClinVar), R408W (VarID 577, Pathogenic in ClinVar). PubMed:9429153

Curation History

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