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_000277.1(PAH):c.805A>C (p.Ile269Leu)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA229775

102842 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 980fb510-b83f-4177-95ab-dc11302d825a

Approved on: 2018-12-10

Published on: 2019-05-04

HGVS expressions

NM_000277.1:c.805A>C

NM_000277.1(PAH):c.805A>C (p.Ile269Leu)

NC_000012.12:g.102852852T>G

CM000674.2:g.102852852T>G

NC_000012.11:g.103246630T>G

CM000674.1:g.103246630T>G

NC_000012.10:g.101770760T>G

NG_008690.1:g.69751A>C

NG_008690.2:g.110559A>C

NM_000277.2:c.805A>C

NM_001354304.1:c.805A>C

NM_000277.3:c.805A>C

ENST00000307000.7:c.790A>C

ENST00000549247.6:n.564A>C

ENST00000553106.5:c.805A>C

Pathogenic

PM3_Very Strong PP4_Moderate PP3 PM2

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.805A>C (p.Ile269Leu) variant in PAH has been reported in multiple individuals with PAH deficiency, including non-PKU HPA (BH4 deficiency excluded). (PP4_Moderate; PMID10767174, PMID 2350059). This variant has an extremely low allele frequency in ExAC and gnomAD (PM2; ENF=0.00013). This variant was detected in trans with multiple known pathogenic variants: PMID 9521426: c.842+3G>C; PMID 10767174: R261X; PMID 14726806: E280K; PMID 21871829: IVS10-11G>A (PM3_Very-strong). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Very-strong, PP4_Moderate, PM2, PP3.

PM3_Very Strong

PMID 9521426: c.842+3G>C (VarID 102871, LP)/c.805A>C (I269L). Observed in trans. PMID: 10767174: detected with R261X (P). PMID: 14726806. detected with E280K, known pathogenic. PMID: 21871829. detected with IVS10-11G>A, known pathogenic.

Patients 19, 20: R261X/I269L (previously described). Patient 55: p.I269L/IVS10nt-11G>A (VarID 607, pathogenic) PubMed:21871829

The genotype combination of an I269L allele with a classic PKU allele (R261X) was associated with a non-PKU hyperphenylalaninemia phenotype. (VarID 610, Pathogenic). PubMed:10767174

E280K (VarID 580, Pathogenic)/I269L PubMed:14726806

PMID 9521426: c.842+3G>C/c.805A>C (I269L) in one patient with non-PKU HPA PubMed:9521426

PP4_Moderate

PMID10767174: I269L in one patient with non-PKU HPA (300 uM). BH4 deficiency evaluated. PMID 2350059: identified in one patient with non-PKU HPA.

117 patients. Every hyperphenylalaninemic child was systematically evaluated for urinary pterin levels and for dihydropteridine reductase activity, in order to discriminate between tetrahydrobiopterin and PAH deficiency. Patient F46: pretreatment Phe (300 uM). genotype: I269L/R261X. PubMed:10767174

PMID 9521426: I269L in one patient with non-PKU HPA (F100). The occurrence of defects involving homeostasis or synthesis of the phenylalanine hydroxylase cofactor (BH4) was ruled out by dosing the urinary pterins as well as by identification of mutations in the PAH gene. PubMed:9521426

PP3

Multiple lines of computational evidence support a deleterious effect: SIFT (D), PolyPhen-2 (P), MutationTaster (D), REVEL=0.799

PM2

extremely low frequency in ExAC and gnomAD (ENF=0.00013)

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.