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>A (p.Gly247Ser)

CA229730

102815 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 0a93d02f-63e4-404b-812c-888db7fadaa6

HGVS expressions

NM_000277.2:c.739G>A

NM_000277.2(PAH):c.739G>A (p.Gly247Ser)

NC_000012.12:g.102852918C>T

CM000674.2:g.102852918C>T

NC_000012.11:g.103246696C>T

CM000674.1:g.103246696C>T

NC_000012.10:g.101770826C>T

NG_008690.1:g.69685G>A

NG_008690.2:g.110493G>A

NM_000277.1:c.739G>A

NM_001354304.1:c.739G>A

NM_000277.3:c.739G>A

ENST00000307000.7:c.724G>A

ENST00000549247.6:n.498G>A

ENST00000553106.5:c.739G>A

Likely Pathogenic

PP3 PM3 PM2 PP4_Moderate

PM5

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.739G>A (p.Gly247Ser) variant in PAH was reported in 1 patient with classical PKU, BH4 deficiency excluded. (PMID: 16256386, 25456745) It was detected with T200Nfs, (pathogenic per PAH VCEP). This variant is absent from ExAC, 1000G, gnomAD, and ESP. It 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: PM2, PP4_Moderate, PM3, PP3.

PP3

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

PM3

Detected with T200Nfs, pathogenic per ClinGen Metabolic workgroup. PMID: 25456745

Patient genotype: G247S + T 200fsX6 (VarID 102748). PubMed:25456745

PM2

Absent from ExAC, 1000G, gnomAD, ESP

PP4_Moderate

Found in 1 patient with classical PKU. BH4 deficiency excluded. PMID: 16256386, 25456745.

A total of 51 unrelated patients with HPA that had been diagnosed by conventional biochemical methods (blood Phe > 120 μmol/L) and one healthy control sample were enrolled in this study. Samples were divided into two groups: a standard group and a test group. A standard cohort of 14 patients and one healthy control sample had previously undergone genotype analysis of PAH or PTS using Sanger DNA sequencing in the Department of Medical Genetics at the Capital Institute of Pediatrics. Patient from Song et al was included in the standard cohort. Custom AmpliSeq™ panel targets the coding DNA sequence (CDS), flanking introns, 5′ untranslated region (UTR) and 3′ UTR of PAH, PTS, GCH1, PCBD1, and QDPR. No additional pathogenic variants were detected in this patient. PubMed:25456745

Found in patient with classical PKU. PubMed:16256386

PM5

G247V Likely Pathogenic

Approved on: 2018-12-10

Published on: 2019-04-06

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