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_000277.1:c.800A>G

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CA16020862

556296 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: cfc277f3-4908-4b72-91d5-1b6868950557

Approved on: 2018-12-10

Published on: 2019-04-05

HGVS expressions

NM_000277.1:c.800A>G

NC_000012.12:g.102852857T>C

CM000674.2:g.102852857T>C

NC_000012.11:g.103246635T>C

CM000674.1:g.103246635T>C

NC_000012.10:g.101770765T>C

NG_008690.1:g.69746A>G

NG_008690.2:g.110554A>G

NM_000277.2:c.800A>G

NM_001354304.1:c.800A>G

NM_000277.3:c.800A>G

ENST00000307000.7:c.785A>G

ENST00000549247.6:n.559A>G

ENST00000553106.5:c.800A>G

Pathogenic

PS3 PP3 PM2 PP4_Moderate PM3

PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.800A>G (p.Gln267Arg) variant in PAH has been reported in 1 individual with Classic PKU (BH4 deficiency excluded) and was detected with G257V which is pathogenic per the ClinGen PAH VCEP (PP4_Moderate, PM3; PMID: 24401910). This variant is absent in population databases (PM2). This variant has 1.1% enzyme activity (PS3; PMID: 24401910). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM2, PM3, PP3.

PS3

Relative PAH activity of Q267R mutant was 1.1% of wt. PMID: 24401910

An expression plasmid carrying the PAH cDNA sequence under the transcriptional control of SV40 promoter was used for PAH activity assay. The expression plasmids were individually transfected into COS-1 cells by the calcium phosphate method. PAH activity was assayed in crude extracts of the transfected cells by measuring the conversion of L-[14C]phenylalanine to L-[14C]tyrosine using either natural cofactor BH4 or synthetic cofactor 6MPH4. Residual PAH enzymatic activity was determined from at least three sets of lysates of transfected COS-1 cells using independently prepared plasmid DNAs. Relative PAH activity of Q267R was 1.1% of wt. PubMed:24401910

PP3

Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.979.

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

Q267R reported in 1 Taiwanese patient with classical PKU. BH4 deficiency was ruled out. PMID: 24401910

In this study of the PAH mutation spectrum in the Taiwanese population, 139 alleles were identified including 34 different mutations. Q267R is first reported in this study. Seventy-one PAH-deficient families in Taiwan were included. Majority (63 families) of the subjects were identified through neonatal screening. The remaining subjects were from schools of special education (4 families) and from outpatient clinics (4 families). BH4 deficiency has been ruled out in these patients. Patient carrying compound heterozygous mutation of Q267R/G257V manifested classical PKU phenotype. PubMed:24401910

PM3

Patient Genotype: G257V + Q267R. G257V is pathogenic per ClinGen PAH VCEP. PMID: 24401910

Patient (20) Genotype: G257V (VarID 102830) + Q267R. When sequence alteration was identified, paternal or maternal origin was determined whenever the parental DNA was available. PubMed:24401910

PM5

3 other variants at this codon in ClinVar, all likely pathogenic.

Curation History

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