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_000277.2(PAH):c.699C>A (p.Phe233Leu)

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CA229699

102790 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 334dab92-e6af-4ddc-84fb-6dd73004c37f

Approved on: 2020-11-09

Published on: 2022-02-20

HGVS expressions

NM_000277.2:c.699C>A

NM_000277.2(PAH):c.699C>A (p.Phe233Leu)

NC_000012.12:g.102855143G>T

CM000674.2:g.102855143G>T

NC_000012.11:g.103248921G>T

CM000674.1:g.103248921G>T

NC_000012.10:g.101773051G>T

NG_008690.1:g.67460C>A

NG_008690.2:g.108268C>A

ENST00000553106.6:c.699C>A

ENST00000307000.7:c.684C>A

ENST00000549111.5:n.795C>A

ENST00000553106.5:c.699C>A

NM_000277.1:c.699C>A

NM_001354304.1:c.699C>A

NM_000277.3:c.699C>A

NM_001354304.2:c.699C>A

NM_000277.3(PAH):c.699C>A (p.Phe233Leu)

Pathogenic

PP4_Moderate PM5 PM2 PP3 PM3_Strong

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.699C>A (p.Phe233Leu) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded), detected in trans with pathogenic variants: p.S70del (PMID: 24705691); p.Ala403Val, p.Arg243Gln (PMID: 23500595). This variant is absent in population databases. Computational prediction tools and conservation analysis support a deleterious effect. Another variant at the same amino acid (p.F233I) is interpreted as pathogenic by the ClinGen PAH VCEP. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3.

PP4_Moderate

F233L seen on 4 PKU alleles. PTPS deficiency excluded in 1 patient (PAH, PTS, GCH1, QDPR, PCBD1 and GFRP genes, including 50 bp in the intron-exon boundaries were directly sequenced). PMID: 24705691

PKU patients from four centers in three countries of Great Britain were studied. 490 independent mutant chromosomes were analyzed. F233L was seen on 3 PKU alleles. PubMed:9012412

The cohort study consisted of 93 subjects from 32 families, including 33 patients diagnosed with PKU and two patients diagnosed with BH4 deficiency according to the diagnostic criteria published in Blau et al., 2011. the 39 exons of PAH, PTS, GCH1, QDPR, PCBD1 and GFRP genes, including 50 bp in the intron-exon boundaries were directly sequenced. c.699C>A (F233L) was seen in patient 11 with mild HPA. PubMed:24705691

PM5

p.F233I interpreted as pathogenic by 1 submitter (PAH VCEP: PP4_Moderate, PS3, PM3_strong, PM2, PP3)

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.904

PM3_Strong

Detected in trans with S70del (Pathogenic in ClinVar). PMID: 24705691; p.Ala403Val (P), p.Arg243Gln (P) with p.Phe233Leu (c.699C>A). variable sites in patient genes were aligned with the corresponding sites from the respective parents. PMID: 29316886 3.0 pts

Patient 11 Genotype: c.699C>A, F233L (maternally inherited)/ p.S70del (paternally inherited) PubMed:24705691

Curation History

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