Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computed assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

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

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
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Pathogenic

Met criteria codes 5
PM2 PM5 PP4_Moderate PM3_Strong PP3

Evidence Links 2

Expert Panel

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.
Met criteria codes
PM2
Absent from ExAC, gnomAD, 1000G, ESP
PM5
p.F233I interpreted as pathogenic by 1 submitter (PAH VCEP: PP4_Moderate, PS3, PM3_strong, PM2, 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
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
PP3
Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.904
Curation History
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