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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Variant: NM_000277.2(PAH):c.175G>T (p.Asp59Tyr)

CA229466

102615 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 02b37c3d-2b34-4caf-85b2-f66b5fdc9d32

HGVS expressions

NM_000277.2:c.175G>T

NM_000277.2(PAH):c.175G>T (p.Asp59Tyr)

NC_000012.12:g.102894912C>A

CM000674.2:g.102894912C>A

NC_000012.11:g.103288690C>A

CM000674.1:g.103288690C>A

NC_000012.10:g.101812820C>A

NG_008690.1:g.27691G>T

NG_008690.2:g.68499G>T

ENST00000553106.6:c.175G>T

ENST00000307000.7:c.160G>T

ENST00000546844.1:c.175G>T

ENST00000548677.2:n.262G>T

ENST00000548928.1:n.97G>T

ENST00000549111.5:n.271G>T

ENST00000550978.6:n.159G>T

ENST00000551337.5:c.175G>T

ENST00000551988.5:n.264G>T

ENST00000553106.5:c.175G>T

ENST00000635500.1:n.143G>T

NM_000277.1:c.175G>T

NM_001354304.1:c.175G>T

NM_000277.3:c.175G>T

NM_001354304.2:c.175G>T

NM_000277.3(PAH):c.175G>T (p.Asp59Tyr)

Uncertain Significance

PM2 PM3_Supporting PP4_Moderate

PS3 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.175G>T (p.Asp59Tyr) variant in PAH has been reported in 1 individual with mild hyperphenylalaninaemia (BH4 deficiency excluded). (PP4_Moderate; PMID: 10234516). This variant has is absent in population databases. This variant was detected with A403V (Pathogenic in ClinVar) (PM3_supporting; PMID: 10234516). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting.

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PM3_Supporting

Detected with A403V, known pathogenic variant. PMID: 10234516 When possible, the identified mutations were confirmed by restriction analysis of PCR products amplified again in affected subjects and their parents. The Mendelian inheritance was confirmed when parental samples were available by DGGE or restriction enzyme digestion.

Patient genotype: D59Y/A403V PubMed:10234516

PP4_Moderate

D59Y was detected in 1 patient with MHP (mild hyperphenylalaninaemia). BH4 defects excluded. PMID: 10234516

Analysed 195 PKU patients by DGGE analysis. Patients were considered as having hyperphenylalaninaemia when the serum phenylalanine levels at diagnosis were higher than 120 umol/L and after exclusion of a defect in tetrahydrobiopterin metabolism. D59Y was detected in 1 patient with MHP (mild hyperphenylalaninaemia). PubMed:10234516

PS3

D59Y has 92% of wild type activity. PMID: 21953985

D59Y has 92% of wild type activity PubMed:21953985

PP3

computational evidence is conflicting: SIFT (T), Polyphen-2 (B), MutationTaster (D), REVEL=0.562

Approved on: 2021-02-14

Published on: 2022-06-28

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