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]

Link to SEPIO compliant JSON-LD document

CA16020844

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 41a0839e-668b-4822-b2dc-642647ffe144

HGVS expressions

NM_000277.3:c.699C>G

ENST00000553106.6:c.699C>G

ENST00000307000.7:c.684C>G

ENST00000549111.5:n.795C>G

ENST00000553106.5:c.699C>G

NM_000277.1:c.699C>G

NM_000277.2:c.699C>G

NM_001354304.1:c.699C>G

NM_001354304.2:c.699C>G

NC_000012.12:g.102855143G>C

CM000674.2:g.102855143G>C

NC_000012.11:g.103248921G>C

CM000674.1:g.103248921G>C

NC_000012.10:g.101773051G>C

NG_008690.1:g.67460C>G

NG_008690.2:g.108268C>G

Pathogenic

PP3 PM3_Strong PM5 PM2 PP4_Moderate

PS1

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.699C>G (p.Phe233Leu) variant in PAH has been reported in multiple individuals with moderate/mild PKU (BH4 deficiency excluded). (PMID: 25894915, 26322415). This variant is absent in population databases. This variant was detected with multiple pathogenic/likely pathogenic variants: p.R243Q (PMID: 25894915); p.G247V (PMID: 26322415); c.442-1G>A; p.A434D (PMID: 30050108). Another pathogenic variant at the same amino acid (p.Phe233Ile) is reported (by PAH VCEP). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong, PM5, PP3.

PP3

Deleterious effect predicted by SIFT, Polyphen2, MutationTaster, REVEL=0.904

PM3_Strong

c.699C>G detected with R243Q (Pathogenic in ClinVar). parental analysis not reported PMID: 25894915; c.[699C>G];[740G>T]/p.[F233L];[G247V] (P/LP). All mutations identified in patients were confirmed by analyzing parental DNA PMID: 26322415; p.S349A, c.442-1G>A (P 6 submitters); p.A434D (LP 1 submitter) The validation tests on parents were performed using Sanger sequencing. PMID: 30050108 (3.5 pts)

c.699C>G seen with R243Q (VarID 591, pathogenic) in 1 patient PubMed:25894915

PM5

p.Phe233Ile pathogenic by PAH VCEP

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

c.699C>G seen on 1 allele in a patient with moderate PKU (serum Phe 515) PMID: 25894915. Detected in a patient with mild PKU. BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PMID: 26322415

We systematically investigated all 13 exons of the PAH gene and their flanking introns in 31 unrelated patients and their parents using next-generation sequencing (NGS). Patients with BH4 cofactor deficiency were excluded. A total of 33 different variants were identified in 58 of 62 mutant PAH alleles. One novel variant was identified in this study—c.699C > G. PubMed:25894915

PS1

c.699C>A (p.Phe233Leu), likely pathogenic by PAH VCEP, no interpretation in ClinVar

Approved on: 2020-08-07

Published on: 2021-09-26

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