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.841C>T (p.Pro281Ser)

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Curation History
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CA220587

92749 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4bb0b9e5-fa14-4fb0-bac1-1bcae3cc23b8

Approved on: 2018-08-10

Published on: 2019-08-17

HGVS expressions

NM_000277.1:c.841C>T

NM_000277.1(PAH):c.841C>T (p.Pro281Ser)

NC_000012.12:g.102852816G>A

CM000674.2:g.102852816G>A

NC_000012.11:g.103246594G>A

CM000674.1:g.103246594G>A

NC_000012.10:g.101770724G>A

NG_008690.1:g.69787C>T

NG_008690.2:g.110595C>T

NM_000277.2:c.841C>T

NM_001354304.1:c.841C>T

NM_000277.3:c.841C>T

ENST00000307000.7:c.826C>T

ENST00000549247.6:n.600C>T

ENST00000553106.5:c.841C>T

ENST00000635477.1:n.2C>T

Likely Pathogenic

PP4_Moderate PM2 PP3 PM3_Strong

PM5

Evidence Links 3

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: 1 allele in ExAC ; PP3: tools predict damaging ; PP4_Moderate: P281S Identified in at least one patient with classic PKU. BH4 deficiency excluded. (PMID:15589814); PM3_Strong: Detected with c.1315+1G>A & p.Arg243Ter, pathogenic in ClinVar (PMID:26666653; PMID:27121329). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong).

PP4_Moderate

P281S Identified in at least one patient with classic PKU. BH4 deficiency excluded.

known mutations in the PAH gene, and pterin profile and dihydropteridine reductase activity excluding a primary defect in BH4 metabolism. Patient 54 with Classic PKU was homozygous for P281S. Phe before BH4 loading: 1145 umol/L. PubMed:15589814

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM3_Strong

Detected with c.1315+1G>A & p.Arg243Ter, pathogenic in ClinVar

Patient genotype: c. [841C>T]; [1315+1G>A] (VarID576, Pathogenic). PubMed:26666653

Patient genotype: p.[Arg243*];[Pro281Ser]. (VarID588, Pathogenic) PubMed:27121329

PM5

P281L is Pathogenic in ClinVar, LP by PAHEP

Curation History

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