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_000277.2(PAH):c.812A>T (p.His271Leu)

CA267675

120287 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d8dab33d-d9aa-45d0-8e54-f50e90d27dd5

HGVS expressions

NM_000277.2:c.812A>T

NM_000277.2(PAH):c.812A>T (p.His271Leu)

NC_000012.12:g.102852845T>A

CM000674.2:g.102852845T>A

NC_000012.11:g.103246623T>A

CM000674.1:g.103246623T>A

NC_000012.10:g.101770753T>A

NG_008690.1:g.69758A>T

NG_008690.2:g.110566A>T

NM_000277.1:c.812A>T

NM_001354304.1:c.812A>T

NM_000277.3:c.812A>T

ENST00000307000.7:c.797A>T

ENST00000549247.6:n.571A>T

ENST00000553106.5:c.812A>T

Uncertain Significance

PP4_Moderate PP3 PM2

PM5

Evidence Links 1

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: Absent from ExAC, gnomAD, 1000G, ESP; PP3: Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.957; PP4_Moderate: H271L seen in a Chinese PKU patient. BH4 deficiencies excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:26503515). In summary this variant meets criteria to be classified as uncertain significance 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).

PP4_Moderate

H271L seen in a Chinese PKU patient. BH4 deficiencies excluded. Upgraded per ClinGen Metabolic workgroup.

A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. These patients were diagnosed at birth either through a neonatal screening program or based on clinical presentation. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. H271L was detected in 1 patient. PubMed:26503515

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.957

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PM5

2 other variants at this codon in ClinVar, but no clinical significance provided

Approved on: 2018-08-10

Published on: 2019-04-05

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