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]

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Variant: NM_000277.1(PAH):c.665A>G (p.Asp222Gly)

CA229679

102775 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: c66e7bd4-9577-4574-a507-e80644413b0d

Approved on: 2020-07-09

Published on: 2021-09-19

HGVS expressions

NM_000277.1:c.665A>G

NM_000277.1(PAH):c.665A>G (p.Asp222Gly)

NC_000012.12:g.102855177T>C

CM000674.2:g.102855177T>C

NC_000012.11:g.103248955T>C

CM000674.1:g.103248955T>C

NC_000012.10:g.101773085T>C

NG_008690.1:g.67426A>G

NG_008690.2:g.108234A>G

ENST00000553106.6:c.665A>G

ENST00000307000.7:c.650A>G

ENST00000549111.5:n.761A>G

ENST00000553106.5:c.665A>G

NM_000277.2:c.665A>G

NM_001354304.1:c.665A>G

NM_000277.3:c.665A>G

NM_001354304.2:c.665A>G

Likely Pathogenic

PP4_Moderate PM2 PM3_Strong

PP3 PM5

Evidence Links 6

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.665A>G (p.Asp222Gly) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 24510552, 9429153); One had BH4 cofactor deficiency excluded (PMID: 15589814). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: p.A104D (PMID: 9429153); p.R408W (PMID: 15589814); c.1066-11G>A (PMID: 23842451); p.L48S (PMID: 25757997); p.I65T (PMID: 16165389). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_strong.

PP4_Moderate

D222G found on 3 PKU patients (PMID: 24510552, PMID: 9429153). One had BH4 cofactor deficiency excluded (PMID: 15589814).

GenomicDNA was isolated from total blood of 34 MHP and eight mild PKU probands from unrelated Polish families. D222G was found in 1 patient with borderline mild PKU (serum Phe 545 umol/l pretreatment, 121-605 on diet). PubMed:9429153

Patient 14.1 Identified on neonatal screening. Phe at diagnosis was 950, variant PKU (plasma Phe 1200–600 uM). Genotype D222G/IVS10-11G > A. PubMed:12409276

64 patients with phenylketonuria. Inclusion criteria for patients were as follows: (a) known mutations in the PAH gene or mutations in the course of investigation and pterin profile and dihydropteridine reductase activity excluding a primary defect in BH4 metabolism. Patient 27 had moderate PKU (Phe levels on unrestricted nutrition 600-1200 umol/L and tolerance: 350–400 mg Phe/day), and D222G/R408W. PubMed:15589814

1 PKU patient had genotype c.1066-11G>A1/p.D222G PubMed:23842451

For 35 PKU children patients and 50 healthy individuals, all exons and promoters of the PAH gene were analyzed with PCR and direct sequencing. D222G was found in PKU patient. PubMed:24510552

PM2

Absent in ExAC, gnomAD, 1000G, ESP

PM3_Strong

D222G found with A104D parental analysis not performed (PMID: 9429153); R408W parental analysis not reported (PMID: 15589814); c.1066-11G>A parental analysis not reported (PMID: 23842451); L48S parental analysis not reported (PMID: 25757997); p.I65T parental analysis not reported (PMID: 16165389); p.S16* validation tests on parents were performed (All Pathogenic in ClinVar) 3.5 pts

D222G found in trans with A104D (VarID 102650, Pathogenic in ClinVar) in 1 PKU patient. PubMed:9429153

D222G found in trans with R408W (VarID 577, pathogenic in ClinVar) in 1 PKU patient PubMed:15589814

1 PKU patient had genotype c.1066-11G>A1/p.D222G PubMed:23842451

Subject 8 had mild PKU and genotype L48S/D222G PubMed:25757997

PP3

Predicted deleterious in SIFT and MutationTaster, predicted benign in Polyphen2

PM5

p.Asp222Val (varID 102776) clinical significance not provided in ClinVar

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