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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CA6748738

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6d49ae10-1024-4b21-9ee6-f82dae60d390

HGVS expressions

NM_001354304.2:c.1136T>C

NC_000012.12:g.102843709A>G

CM000674.2:g.102843709A>G

NC_000012.11:g.103237487A>G

CM000674.1:g.103237487A>G

NC_000012.10:g.101761617A>G

NG_008690.1:g.78894T>C

NG_008690.2:g.119702T>C

ENST00000553106.6:c.1136T>C

ENST00000307000.7:c.1121T>C

ENST00000553106.5:c.1136T>C

NM_000277.1:c.1136T>C

NM_000277.2:c.1136T>C

NM_001354304.1:c.1136T>C

NM_000277.3:c.1136T>C

Uncertain Significance

PP4_Moderate PP3 PM2

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1136T>C (p.Val379Ala) PAH variant has been reported in at least two mild HPA probrands with exclusion of BH4 deficiency (PMID: 21307867). This variant is found at an extremely low frequency (0.0001737) in the gnomAD Latino population. It is a missense variant predicted deleterious by SIFT (damaging) and MutationTaster (disease causing), with a REVEL score of 0.796. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3, PP4_moderate.

PP4_Moderate

Two mild HPA probrands from PMID: 21307867 meet criteria for PP4_moderate with PHE levels of ~1.5mmol/L and exclusion of BH4 deficiency.

PP3

This variant is predicted deleterious by SIFT (damaging), MutationTaster (disease causing), and has a REVEL score of 0.796.

PM2

This variant is found at an extremely low frequency with a MAF of 0.0001737 (6/34544 alleles) in the gnomAD Latino population. This is below the <0.02% threshold.

Approved on: 2020-05-08

Published on: 2021-04-23

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