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.969A>G (p.Thr323=)

CA229881

102917 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: dced0f30-619d-4db7-a0e4-90e7c538b7dc

Approved on: 2021-02-13

Published on: 2021-04-09

HGVS expressions

NM_000277.3:c.969A>G

NM_000277.3(PAH):c.969A>G (p.Thr323=)

NC_000012.12:g.102846895T>C

CM000674.2:g.102846895T>C

NC_000012.11:g.103240673T>C

CM000674.1:g.103240673T>C

NC_000012.10:g.101764803T>C

NG_008690.1:g.75708A>G

NG_008690.2:g.116516A>G

ENST00000307000.7:c.954A>G

ENST00000553106.5:c.969A>G

NM_000277.1:c.969A>G

NM_000277.2:c.969A>G

NM_001354304.1:c.969A>G

NM_001354304.2:c.969A>G

Uncertain Significance

PM2 BS3_Supporting

BP7 BP2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.969A>G (p.Thr323=) variant in PAH has been found in a patient with PAH deficiency in cis with pathogenic variant IVS2–13T→G (PMID: 10394930). This variant has an extremely low frequency in gnomAD (MAF=0.00001). Splicing predictions are conflicting (HSF/MaxENT: probably no impact; TRAP 0.831: probably damaging). A functional study shows no significant effect on protein activity as compared to wild type (Relative PAH activity 114 +/-18, PMID: 18590700). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, BS3_supporting.

PM2

extremely low frequency in gnomAD (MAF=0.00001)

BS3_Supporting

Relative PAH activity 114+/-18 PMID: 18590700

significant higher activity in the Intinc system compared to the cDNA system. Relative PAH activity 114+/-18 PubMed:18590700

BP7

HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. MaxENT:+24.45. TRAP 0.831 probably damaging.

BP2

IVS2–13T→G has been found in cis with the novel mutation c.969A→G PMID: 10394930

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