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  • See Evidence submitted by expert panel for details.

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

CA229484

102627 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: ae4e41b8-65ec-4a05-80d4-aa542e0bb9bd
Approved on: 2020-07-02
Published on: 2021-07-09

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
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Pathogenic

Met criteria codes 6
PP1 PP3 PP4_Moderate PM2 PM5 PM3_Strong
Not Met criteria codes 2
BS3 PS3

Evidence Links 3

Expert Panel

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.
Met criteria codes
PP1
R68G/R243Q in 2 siblings with mild PKU

PP3
Predicted deleterious in SIFT, PolyPhen2, MutationTaster
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

PM2
Absent from ExAC, gnomAD, 1000G, ESP.
PM5
R68S Pathogenic in ClinVar
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

Not Met criteria codes
BS3
100% Enzyme activity, in vitro expression analysis

PS3
100% Enzyme activity, in vitro expression analysis

Curation History
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