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]

Variant: NM_000277.3(PAH):c.1144T>C (p.Phe382Leu)

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CA386493225

556882 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 764ebb0c-185b-4e39-9493-964818951434

Approved on: 2021-02-13

Published on: 2023-01-28

HGVS expressions

NM_000277.3:c.1144T>C

NM_000277.3(PAH):c.1144T>C (p.Phe382Leu)

NC_000012.12:g.102843701A>G

CM000674.2:g.102843701A>G

NC_000012.11:g.103237479A>G

CM000674.1:g.103237479A>G

NC_000012.10:g.101761609A>G

NG_008690.1:g.78902T>C

NG_008690.2:g.119710T>C

ENST00000553106.6:c.1144T>C

ENST00000307000.7:c.1129T>C

ENST00000549247.6:n.903T>C

ENST00000551114.2:n.806T>C

ENST00000553106.5:c.1144T>C

ENST00000635477.1:n.248T>C

ENST00000635528.1:n.659T>C

NM_000277.1:c.1144T>C

NM_000277.2:c.1144T>C

NM_001354304.1:c.1144T>C

NM_001354304.2:c.1144T>C

Pathogenic

PS3 PP3 PM3 PM2 PP4_Moderate

PS1 PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1144T>C (p.Phe382Leu) variant in PAH has been reported in 1 homozygous individual with mild HPA and BH4 deficiency excluded (PP4_Moderate; 0.5 points; PMID: 21147011) and has also been reported in a patient from southern Italy (PMID: 17096675; PMID: 18346471) with mild hyperphenylalanemia (serum Phe 182 umol/L; not specified if BH4 deficiency excluded), who harbored it in presumed trans with the p.R252W variant (Pathogenic in ClinVar by 10 submitters, variation ID 584) (0.5 points) (PM3, 1 point total). This variant was absent in population databases (PM2). Expressed in COS-1 cells, this variant has 18% enzyme activity (PS3; PMID: 22698810). Computational prediction tools suggest that the variant may impact the protein (REVEL = 0.89; PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS3, PM2, PM3, PP4_moderate, PP3.

PS3

Expression on COS-1 cells found 18% residual activity for this variant compared to WT.

The expression of c.1144T>C (p.F382L) mutant protein in COS-1 cells showed reduced activity compared to wild type PAH protein. Residual activity for mutant p.F382L activity was 18%. Additionally, RT-PCR in patient cells and minigene assay in COS-1 cells suggest that this variant causes skipping of exon 11 which causes NMD. PubMed:22698810

PP3

Predicted damaging in SIFT, PolyPhen2, and Mutation Taster, REVEL = 0.89.

PM3

One c.1146T>C homozygote has been described with mild HPA (PMID: 21147011). In addition, the variant has also been reported in a patient from southern Italy (PMID: 17096675; PMID: 18346471) with mild hyperphenylalanemia (serum Phe 182 umol/L; not specified if BH4 deficiency excluded), who harbored it in presumed trans with the p.R252W variant (Pathogenic in ClinVar by 10 submitters, variation ID 584) (0.5 points)

PM2

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PP4_Moderate

At least one mild HPA patient has been reported (PMID: 21147011) mild HPA (Phe between 120 and 600 μM). BH4 deficiency was excluded by sequencing of PTS and QDPR.

PS1

The likely pathogenic variant c.1146C>G (p.Phe382Leu) with the same amino acid change has been reported in at least one proband. It is not evaluated here to avoid circularity.

PM5

The variant c.1144T>A (p.Phe382Ile), reported in PMID: 29499199, occurs at the same amino acid residue but it is not present in ClinVar and its pathogenicity has not been evaluated.

Curation History

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