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.889C>T (p.Arg297Cys)

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Curation History
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CA229836

102885 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d25191fc-95b0-4444-8fc1-9115fe7c811c

Approved on: 2019-07-14

Published on: 2019-07-14

HGVS expressions

NM_000277.2:c.889C>T

NM_000277.2(PAH):c.889C>T (p.Arg297Cys)

NC_000012.12:g.102851710G>A

CM000674.2:g.102851710G>A

NC_000012.11:g.103245488G>A

CM000674.1:g.103245488G>A

NC_000012.10:g.101769618G>A

NG_008690.1:g.70893C>T

NG_008690.2:g.111701C>T

NM_000277.1:c.889C>T

NM_001354304.1:c.889C>T

NM_000277.3:c.889C>T

ENST00000307000.7:c.874C>T

ENST00000549247.6:n.648C>T

ENST00000551114.2:n.551C>T

ENST00000553106.5:c.889C>T

ENST00000635477.1:n.50C>T

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3 PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.889C>T (p.R297C) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded: PMID: 8807331, 21307867). It was detected in trans with the pathogenic variant IVS12nt1 (VarID576; PMID 8807331). This variant has an extremely low allele frequency in gnomAD (7/245782). Two other missense variants at the same codon are pathogenic. (92750). Computational prediction tools and conservation analysis suggest that the c.889C>T variant may impact the protein. Overall, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3, PM5, PP4_moderate.

PP4_Moderate

Detected in a patient with classic PKU (Serum phenylalanine 472 micromolar). Detected in a patient with mild HPA, BH4 deficiency ruled out ( PMID: 21307867)

Detected in a patient with classic PKU (table 2). Serum phenylalanine 472 micromolar. PubMed:8807331

Detected in a patient with mild HPA (serum phenylalanine level higher than 0.18mM). on the basis of absence of neurologic deterioration on a low phenylalanine diet, analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine. Mild PKU and mild HPA are characterized by serum phenylalanine concentrations of 0.6–1.2 and 0.18–0.6 mM, respectively, without a phenylalanine-restricted diet. PubMed:21307867

PP3

REVEL=0.824

PM2

gnomAD 7/245782

PM3

Detected in trans with IVS12nt1, VarID576, Pathogenic (PMID 8807331).

Detected in trans with a splicing mutation in a patient with classic PKU (table 2). Serum phenylalanine 472 micromolar. PubMed:8807331

Detected in the homozygous state in 1 patient. Segregation analysis was done to rule out the presence of large genomic rearrangements. PubMed:27121329

PM5

p.Arg297His: ClinVar 92750

Curation History

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