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]

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Variant: NM_000277.2(PAH):c.739G>C (p.Gly247Arg)

CA229732

102816 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3b4d8605-fad8-4121-9f56-2b0ecf63eb12

HGVS expressions

NM_000277.2:c.739G>C

NM_000277.2(PAH):c.739G>C (p.Gly247Arg)

NC_000012.12:g.102852918C>G

CM000674.2:g.102852918C>G

NC_000012.11:g.103246696C>G

CM000674.1:g.103246696C>G

NC_000012.10:g.101770826C>G

NG_008690.1:g.69685G>C

NG_008690.2:g.110493G>C

NM_000277.1:c.739G>C

NM_001354304.1:c.739G>C

NM_000277.3:c.739G>C

ENST00000307000.7:c.724G>C

ENST00000549247.6:n.498G>C

ENST00000553106.5:c.739G>C

Likely Pathogenic

PM3_Strong 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

The c.739G>C (p.Gly247Arg) variant in PAH has been reported in 3 patients with PAH deficiency, with BH4 deficiency assessed in 2 patients. PMID: 21307867, 18985011, 16256386. It was detected with known pathogenic variants R413P (PMID: 16256386) and V388M (PMID: 18985011). It was absent from ExAC, gnomAD, 1000G, and ESP. This variant is predicted deleterious in SIFT, Polyphen2, MutationTaster, and REVEL=0.981. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_Moderate, PP3.

PM3_Strong

Detected with R413P (PMID: 16256386) and V388M (PMID: 18985011).

Patient genotype: p.Gly247Arg/p.Val388Met (VarID 619, Pathogenic). Blood samples were collected from the patients and their family members. PubMed:18985011

Patient genotype: G247R+R413P (VarID 592, Pathogenic) PubMed:16256386

PP3

Predicted deleterious in SIFT, Polyphen2, MutationTaster. REVEL=0.981.

PP4_Moderate

Detected in 1 classic PKU Chinese patient, a variant PKU Korean patient, and A Japanese PKU patient. BH4 deficiency assessed in Korean and Japanese patients. PMID: 21307867, 18985011, 16256386

This study enrolled 203 Japanese residents with a serum phenylalanine level higher than 0.18mM. PAH deficiency was diagnosed at the participating institutions 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. G247R was detected on 1 allele. PubMed:21307867

Thirty-three unrelated patients with PAH deficiency were recruited from the Korean PKU family support group. Biochemical diagnosis was based on measurement of the plasma phenylalanine concentration before starting a phenylalanine-restricted diet. Urinary pterin analyses and dihydropteridine reductase (DHPR) assays were performed to exclude 6-pyruvoyltetrahydropterin synthase (PTPS) deficiencies. Patient 29, plasma Phe 965, G247R detected. PubMed:18985011

A total of 185 patients with PAH deficiency in 185 independent families from Northern China are included in this study. PAH deficiency was diagnosed by conventional biochemical methods. G247R was detected in 1 patient with classic PKU. PubMed:16256386

PM2

Absent from ExAC, gnomAD, 1000G, ESP.

PM5

G247V Likely Pathogenic in ClinVar

Approved on: 2018-12-10

Published on: 2019-04-06

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