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.800A>T (p.Gln267Leu)

Curation Version - 1.0
Curation History
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CA354145

225135 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0f298658-69d4-402a-a0d1-47973a683451

Approved on: 2018-08-10

Published on: 2019-04-05

HGVS expressions

NM_000277.2:c.800A>T

NM_000277.2(PAH):c.800A>T (p.Gln267Leu)

NC_000012.12:g.102852857T>A

CM000674.2:g.102852857T>A

NC_000012.11:g.103246635T>A

CM000674.1:g.103246635T>A

NC_000012.10:g.101770765T>A

NG_008690.1:g.69746A>T

NG_008690.2:g.110554A>T

NM_000277.1:c.800A>T

NM_001354304.1:c.800A>T

NM_000277.3:c.800A>T

ENST00000307000.7:c.785A>T

ENST00000549247.6:n.559A>T

ENST00000553106.5:c.800A>T

Uncertain Significance

PP3 PP4_Moderate PM2

PM5

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD ( 0.00001, 0.000004063); PP3: Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.975; PP4_Moderate: Q267L found in 1 Japanese PKU allele and in 1 Chinese PKU patient. Analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine was performed in the Japanese study. Upgraded per ClinGen Metabolic workgroup. (PMID:21307867; PMID:24078561; PMID:26503515). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate).

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.975

PP4_Moderate

Q267L found in 1 Japanese PKU allele and in 1 Chinese PKU patient. Analysis of dihydropteridine reductase activity in red blood cells, biopterin loading test and/or pteridine analysis in urine was performed in the Japanese study. Upgraded per ClinGen Metabolic workgroup.

203 Japanese residents with a serum phenylalanine level higher than 0.18 mM. PAH deficiency was diagnosed 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. Q267L was identified on 1 allele. PubMed:21307867

Q267L reported, likely same patient as Zhang JJ report. PubMed:26503515

A total of 70 patients and their parents were included in this study. All of the 13 exons and flanking introns of the PAH gene were analyzed with DNA sequencing. 4 novel mutations were identified: (L37P, H107R, Q267L, S391T). From ClinVar: Indications for testing was plasma Phe concentration >120 µmol/L, and BH4 deficiency was excluded from this case. PubMed:24078561

PM2

Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD ( 0.00001, 0.000004063)

PM5

2 other variants in this codon in ClinVar, but no clinical significance reported

Curation History

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