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]

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CA16020847

619166 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b3f081ca-4251-4be7-a9c4-acd5f05fb2e7

Approved on: 2018-12-10

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.712A>G

NC_000012.12:g.102852945T>C

CM000674.2:g.102852945T>C

NC_000012.11:g.103246723T>C

CM000674.1:g.103246723T>C

NC_000012.10:g.101770853T>C

NG_008690.1:g.69658A>G

NG_008690.2:g.110466A>G

NM_000277.2:c.712A>G

NM_001354304.1:c.712A>G

NM_000277.3:c.712A>G

ENST00000307000.7:c.697A>G

ENST00000549247.6:n.471A>G

ENST00000553106.5:c.712A>G

Likely Pathogenic

PP4_Moderate PM3 PM2 PP3

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.712A>G (p.Thr238Ala) variant in PAH has been reported in 2 individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 23842451, 26503515). This variant is absent in population databases (PM2). This variant was detected with pathogenic variant p.P281L (PM3; PMID: 23842451). Computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP3.

PP4_Moderate

found in 1 Dutch PKU patient (Phe = 549). PMID: 23842451 and Chinese PKU patient (BH4 deficiency assessed) PMID: 26503515

A total of 796 unrelated patients from 29 separate newborn screening centres of China were enrolled. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. p.T238A, c.712A>G was detected on 2 alleles. PubMed:26503515

Data were collected from 183 patients who participated in the 48-hour BH4 loading test between November 2009 and December 2010 in six Dutch university medical centres. Only patients above four years of age, requiring a Phe restricted diet, and not pregnant or planning a pregnancy were considered for treatment with BH4. Blood Phe concentrations in dried blood spots were measured by the patients’ respective centre laboratory according to standard quantitative methods, with the same method per patient. To calculate the individual mean blood Phe concentration prior to the BH4 introduction, all known values from the year preceding the BH4 loading test were used, with a minimum of four measurements; alternatively, the period was extended to two years or this value was considered missing. T238A was identified in 1 patient with baseline Phe level of 549 PubMed:23842451

PM3

found with P281L (Pathogenic in ClinVar) PMID: 23842451

Patient genotype: T238A/P281L (VarID 589, Pathogenic in ClinVar) PubMed:23842451

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP3

Predicted deleterious in SIFT, Polyphen2, mutation taster. REVEL=0.949

Curation History

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