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

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CA220590

92750 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

Pathogenic

PS3 PP4_Moderate PP3 PM2 PM3_Strong

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

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.

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).

Table 2: RA (percent of in vitro activity relative to the wild-type control): 21 PubMed:24401910

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

Detected in 1 patient. BH4 deficiency has been ruled out. PubMed:24401910

Detected in 6 patients with mild hyperphenylalaninemia (Phe level 327-527). The patients were classified according to Guttler. PubMed:9298832

PP3

REVEL=0.64; SIFT and polyphen pathogenic.

PM2

gnomAD 2/245792

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.

Table 2 (31) R413P + R297H (VarID: 592, Pathogenic). When sequence alteration was identified, paternal or maternal origin was determined whenever the parental DNA was available. PubMed:24401910

Detected in trans with pathogenic p.R408W (ClinVar: 577) in 4 patients. Table 1 Also IVS2 (c.168+5G>A; VARID 102606, LP); R252W (VarID 584, P). Parental analysis not performed. PubMed:9298832

Curation History

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