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_000277.3(PAH):c.443G>T (p.Gly148Val)

CA16020791

552657 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5c41ff75-cc92-448f-8fbd-6718561a4dac

Approved on: 2020-01-26

Published on: 2021-02-12

HGVS expressions

NM_000277.3:c.443G>T

NM_000277.3(PAH):c.443G>T (p.Gly148Val)

NM_000277.1:c.443G>T

NM_000277.2:c.443G>T

NM_001354304.1:c.443G>T

NM_001354304.2:c.443G>T

ENST00000307000.7:c.428G>T

ENST00000549111.5:n.539G>T

ENST00000551988.5:n.530+10800G>T

ENST00000553106.5:c.443G>T

NC_000012.12:g.102866662C>A

CM000674.2:g.102866662C>A

NC_000012.11:g.103260440C>A

CM000674.1:g.103260440C>A

NC_000012.10:g.101784570C>A

NG_008690.1:g.55941G>T

NG_008690.2:g.96749G>T

Likely Pathogenic

PP3 PM2 PM3 PP4_Moderate

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.443G>T (p.Gly148Val) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID: 27121329, 26503515). This variant is absent in population databases (PM2). This variant was detected in trans with pathogenic variant p.Ser349Pro. Computational evidence supports 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.

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster, REVEL=0.942

PM2

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

PM3

Detected in trans with p.Ser349Pro (pathogenic 5 submitters). Segregation analysis was done. PMID: 27121329

PP4_Moderate

Detected in a patient with classic PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. PMID: 27121329

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