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.832A>G (p.Thr278Ala)

CA229801

102861 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 67fbae05-2747-47fb-8f90-eb6e3ece3108

HGVS expressions

NM_000277.2:c.832A>G

NM_000277.2(PAH):c.832A>G (p.Thr278Ala)

ENST00000553106.6:c.832A>G

ENST00000307000.7:c.817A>G

ENST00000549247.6:n.591A>G

ENST00000553106.5:c.832A>G

NM_000277.1:c.832A>G

NM_001354304.1:c.832A>G

NM_000277.3:c.832A>G

NM_001354304.2:c.832A>G

NC_000012.12:g.102852825T>C

CM000674.2:g.102852825T>C

NC_000012.11:g.103246603T>C

CM000674.1:g.103246603T>C

NC_000012.10:g.101770733T>C

NG_008690.1:g.69778A>G

NG_008690.2:g.110586A>G

Likely Pathogenic

PM3_Supporting PP4_Moderate PP3 PM5 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.832A>G (p.Thr278Ala) variant in PAH has been reported in multiple individuals with PKU and MHP (BH4 deficiency excluded). (PMID: 26503515, 30050108). This variant is absent in population databases. This variant was detected in the homozygous state in 1 patient (confirmed by parental testing). Computational evidence supports a deleterious effect. Another variant at this same amino acid is interpreted as pathogenic (p.Thr278Ile). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PM3_supporting PP3.

PM3_Supporting

detected in homozygous state in 1 patient. validation tests on parents were performed using Sanger sequencing. 0.5 pts. PMID: 30050108

PP4_Moderate

Seen in 4 individuals with PKU. Biochemical testing data, including plasma phenylalanine (Phe) levels, dihydropteridine reductase activity, urinary biopterin and neopterin ratio, and tetrahydrobiopterin loading, were collected. PMID: 26503515

PP3

Predicted deleterious by Polyphen, MutationTaster, and SIFT.

PM5

T278I interpreted as pathogenic in ClinVar 2 submitters

PM2

Absent from controls in ExAC, 1000 genomes, or gnomAD.

Approved on: 2020-06-11

Published on: 2021-09-24

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