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_000277.3(PAH):c.907T>G (p.Ser303Ala)

CA229842

102890 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: fcbcb1f0-42ce-42c6-8beb-c2791db424ef

HGVS expressions

NM_000277.3:c.907T>G

NM_000277.3(PAH):c.907T>G (p.Ser303Ala)

NC_000012.12:g.102851692A>C

CM000674.2:g.102851692A>C

NC_000012.11:g.103245470A>C

CM000674.1:g.103245470A>C

NC_000012.10:g.101769600A>C

NG_008690.1:g.70911T>G

NG_008690.2:g.111719T>G

ENST00000307000.7:c.892T>G

ENST00000553106.5:c.907T>G

NM_000277.1:c.907T>G

NM_000277.2:c.907T>G

NM_001354304.1:c.907T>G

NM_001354304.2:c.907T>G

Likely Pathogenic

PP4_Moderate PP3 PM2 PM3_Strong

PM5

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.907T>G (p.Ser303Ala) variant in PAH has been reported in 3 individuals with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 23430859, 23500595, 24941924, 27121329). This variant is absent in population databases (PM2). This variant was detected in 2 patients in trans with p.G46S (PMID: 27121329) (this variant is Pathogenic in ClinVar by 5 submitters, ID G46S) and with c.673C>A p.(Pro225Thr) (PMID: 24941924, parental analysis not described) (this variant is Pathogenic in ClinVar by 4 submitters, ID 102779). Computational evidence predicts a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3.

PP4_Moderate

reported in 3 patients with mild PKU, BH4 deficiency ruled out ( PMID: 23430859, 23500595, 24941924, 27121329).

PP3

Predicted deleterious in SIFT, PolyPhen2, MutationTaster. REVEL=0.954

PM2

Absent from controls in ExAC, gnomAD, 1000 Genomes, ESP

PM3_Strong

Detected in 2 patients in trans with p.G46S (P, 2 submitters) PMID: 27121329 (segregation analysis done) and with c.673C>A, p.(Pro225Thr) (P, 1 submitter) PMID: 24941924 parental analysis not described

PM5

p.Ser303Pro: no interpretation provided

Approved on: 2021-01-18

Published on: 2021-04-09

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