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_000277.2(PAH):c.890G>A (p.Arg297His)

CA220590

92750 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
UUID: d5b91f03-15c0-4ffe-9fe6-2a8fca19096a
Approved on: 2019-07-07
Published on: 2019-07-07

HGVS expressions

NM_000277.2:c.890G>A
NM_000277.2(PAH):c.890G>A (p.Arg297His)
NC_000012.12:g.102851709C>T
CM000674.2:g.102851709C>T
NC_000012.11:g.103245487C>T
CM000674.1:g.103245487C>T
NC_000012.10:g.101769617C>T
NG_008690.1:g.70894G>A
NG_008690.2:g.111702G>A
NM_000277.1:c.890G>A
NM_001354304.1:c.890G>A
NM_000277.3:c.890G>A
ENST00000307000.7:c.875G>A
ENST00000549247.6:n.649G>A
ENST00000551114.2:n.552G>A
ENST00000553106.5:c.890G>A
ENST00000635477.1:n.51G>A
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Pathogenic

Met criteria codes 5
PM2 PS3 PP3 PP4_Moderate PM3_Strong

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
The c.890G>A (p.Arg297His) variant in PAH has been reported in 6 patients with PKU, in trans with established pathogenic variants (PMID: 9298832,24401910) with BH4 deficiency excluded in one (PMIDs 24401910 & 9298832). This variant has an extremely low allele frequency in gnomAD (2/245792). The arginine at position 297 is in the C-terminal aromatic amino acid hydroxylase domain, and computational prediction tools and conservation analysis suggest that the c.890G>A variant may impact the protein function. Mutant enzyme activity is 20% as compared to wild type (PMID:24401910). Overall, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM2, PM3_strong, PS3.
Met criteria codes
PM2
gnomAD 2/245792
PS3
21% in vitro activity. To improve on accurate assignment of mutational phenotypes, several mutations were chosen for analysis of in vitro activities. First, residual enzyme activities of a set of missense mutations in transfected COS-1 cells were determined (Figure 1b) and their relative activities (RA), that is, percent of in vitro activity relative to that of wild-type control, were determined (Table 2).

PP3
REVEL=0.64; SIFT and polyphen pathogenic.
PP4_Moderate
Detected in 6 patients with mild hyperphenylalaninemia (Phe level 327-527). PMID: 9298832. Detected in 1 patient with BH4 deficiency ruled out. PMID: 24401910

PM3_Strong
Detected in trans with pathogenic p.R408W in 4 patients, and R252W ( PMID: 9298832) and p.R413P (PMID: 24401910). 3.25 points for unknown phasing.

Curation History
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