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_000277.3(PAH):c.533A>T (p.Glu178Val)

CA229611

102728 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3dea04d4-9b44-473c-b491-d7568f3f774a

Approved on: 2024-09-06

Published on: 2024-09-06

HGVS expressions

NM_000277.3:c.533A>T

NM_000277.3(PAH):c.533A>T (p.Glu178Val)

NC_000012.12:g.102855309T>A

CM000674.2:g.102855309T>A

NC_000012.11:g.103249087T>A

CM000674.1:g.103249087T>A

NC_000012.10:g.101773217T>A

NG_008690.1:g.67294A>T

NG_008690.2:g.108102A>T

ENST00000553106.6:c.533A>T

ENST00000307000.7:c.518A>T

ENST00000549111.5:n.629A>T

ENST00000551988.5:n.554A>T

ENST00000553106.5:c.533A>T

NM_000277.1:c.533A>T

NM_000277.2:c.533A>T

NM_001354304.1:c.533A>T

NM_001354304.2:c.533A>T

Likely Pathogenic

PP3_Moderate PS3_Supporting PM2_Supporting PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specification: ClinGen Phenylketonuria Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PAH Version 2.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.533A>T (p.Glu178Val) variant in PAH has not been reported in the literature/in a patient to our knowledge. This variant is absent in population databases. Computational evidence support a deleterious effect (REVEL= 0.866. Functional studies of this variant have been reported to BioPKU: mutant in vitro expression in COS cells reportedly had 18% enzyme activity as compared to wild type. Another missense change at this amino acid (p.Glu178Gly) is classified as pathogenic. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3_supporting, PM2_supporting, PM5, PP3_moderate.

PP3_Moderate

REVEL = 0.866

PS3_Supporting

Expressed in vitro in COS host cells, 18% enzyme activity as compared to wild type. PMID: 10980574

We present the interpretation of the effect of mutations on PAH activity, based on the available three-dimensional structural information of PAH of 120 mutations associated with PKU that include the 104 ‘classified’ PKU mutations and all the mutations where the corresponding mutant PAH protein has been expressed in vitroCOS host cells, 18% enzyme activity as compared to wild type. Mutations of polar surface residues to hydrophobic ones destabilise the folded state of the protein (mutations T92I and E178V). PubMed:10980574

PM2_Supporting

Absent from controls in gnomAD v2.1.1

PM5

p.Glu178Gly is Pathogenic by 6 submitters and PAH VCEP

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