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

Variant: NM_000277.1(PAH):c.202A>G (p.Arg68Gly)

CA229484

102627 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: ae4e41b8-65ec-4a05-80d4-aa542e0bb9bd

HGVS expressions

NM_000277.1:c.202A>G

NM_000277.1(PAH):c.202A>G (p.Arg68Gly)

ENST00000553106.6:c.202A>G

ENST00000307000.7:c.187A>G

ENST00000546844.1:c.202A>G

ENST00000548677.2:n.289A>G

ENST00000548928.1:n.124A>G

ENST00000549111.5:n.298A>G

ENST00000550978.6:n.186A>G

ENST00000551337.5:c.202A>G

ENST00000551988.5:n.291A>G

ENST00000553106.5:c.202A>G

ENST00000635500.1:n.170A>G

NM_000277.2:c.202A>G

NM_001354304.1:c.202A>G

NM_000277.3:c.202A>G

NM_001354304.2:c.202A>G

NC_000012.12:g.102894885T>C

CM000674.2:g.102894885T>C

NC_000012.11:g.103288663T>C

CM000674.1:g.103288663T>C

NC_000012.10:g.101812793T>C

NG_008690.1:g.27718A>G

NG_008690.2:g.68526A>G

Pathogenic

PP4_Moderate PP1 PP3 PM5 PM2 PM3_Strong

PS3 BS3

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.202A>G (p.Arg68Gly) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PMID: 21147011). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: R243Q (PMID: 10495930); p.R408W (3 patients including 2 siblings); c.842+1G>A (2 patients) PMID: 24350308. Computational prediction tools and conservation analysis support a deleterious effect on the protein. Another missense variant at the same amino acid (p.Arg68Ser) is pathogenic. 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, PP1.

PP4_Moderate

R68G seen in 3 patients with PKU. BH4 deficiency excluded: assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 10495930, 21147011

We describe the phenotypic effects of seven mutations in exon 3 of the PAH gene (R68G). We propose that mutations located between amino acid positions 71 through 94 cause MHP. Patients with genotypes R68G/R243Q (two siblings). PubMed:10495930

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). R68G seen on 1 allele in 1 patient with classic PKU. PubMed:21147011

PP1

R68G/R243Q in 2 siblings with mild PKU

R68G was detected in trans with R243Q in two siblings with mild PKU. Mendelian inheritance was confirmed. PubMed:10495930

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster

PM5

R68S Pathogenic in ClinVar

PM2

Absent from ExAC, gnomAD, 1000G, ESP.

PM3_Strong

R68G detected in trans with R243Q (Pathogenic in ClinVar) PMID: 10495930 p.R408W (c.1222C>T) (3 patients, P-15 submitters); IVS7+1G>A (c.842+1G>A) (2 patients, P) parental analysis not confirmed PMID: 24350308; 3.5 pts

R68G was detected in trans with R243Q (VarID 591, Pathogenic in ClinVar) in two siblings with mild PKU. Mendelian inheritance was confirmed. PubMed:10495930

PS3

100% Enzyme activity, in vitro expression analysis

100% Enzyme activity PubMed:11051201

BS3

100% Enzyme activity, in vitro expression analysis

100% Enzyme activity PubMed:11051201

Approved on: 2020-07-02

Published on: 2021-07-09

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