Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_000277.3(PAH):c.865G>A (p.Gly289Arg)

CA386294434

458082 (ClinVar)

Gene: PAH
Condition: phenylketonuria
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 31011de0-2c21-4068-9234-833617f290cc
Approved on: 2020-10-16
Published on: 2020-10-16

HGVS expressions

NM_000277.3:c.865G>A
NM_000277.3(PAH):c.865G>A (p.Gly289Arg)
NM_000277.1:c.865G>A
NM_000277.2:c.865G>A
NM_001354304.1:c.865G>A
NM_001354304.2:c.865G>A
ENST00000307000.7:c.850G>A
ENST00000549247.6:n.624G>A
ENST00000551114.2:n.527G>A
ENST00000553106.5:c.865G>A
ENST00000635477.1:n.26G>A
NC_000012.12:g.102851734C>T
CM000674.2:g.102851734C>T
NC_000012.11:g.103245512C>T
CM000674.1:g.103245512C>T
NC_000012.10:g.101769642C>T
NG_008690.1:g.70869G>A
NG_008690.2:g.111677G>A
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Pathogenic

Met criteria codes 5
PP4_Moderate PM3 PM2 PS1 PP3

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Phenylketonuria VCEP
This c.865G>A (p.Gly289Arg) variant in PAH was reported in 2 patients with PAH deficiency (PMID: 27121329) detected with the pathogenic variant p.Gly272* and the likely pathogenic variant p.Arg155Cys. DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant has the same amino acid change as a previously established pathogenic variant in ClinVar (Variation ID: 102882). This variant is absent in population databases. Computational evidence for this missense variant supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PS1, PM2, PP4_moderate, PM3, PP3.
Met criteria codes
PP4_Moderate
PP4_moderate: This variant was documented 2 times in patients with PAH deficiency. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity (PMID: 27121329). 27121329, Aldámiz-Echevarría: This variant was documented 2 times in Spanish patients with PAH deficiency. Phenylalanine plasma concentrations >120 μM were reported for all subjects. Tetrahydrobiopterin (BH4) deficiency was excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.
PubMed:27121329
PM3
PM3_met: This variant was detected in trans with the pathogenic PAH variant p.Gly272* in 1 patient with classic PKU. This variant was detected in trans with the likely pathogenic PAH variant p.Arg155Cys in 1 patient with mild hyperphenylalaninemia (MHP)(Arg155Cys variant is also being curated by PAH EP). Parental analysis was performed for both variants to confirm compound heterozygosity. (PMID: 27121329)
PM2
PM2_met: This variant is absent from population databases gnomAD and ExAC.
PS1
PS1_met: Variant has the same amino acid change as a previously established pathogenic variant in ClinVar: NM_000277.3(PAH):c.865G>C (p.Gly289Arg) - Variation ID: 102882 is pathogenic by PAH EP (expert panel)
PP3
PP3_met: Predicted to be damaging (SIFT), probably damaging (PolyPhen2), disease causing (MutationTaster). REVEL=.98
Curation History
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