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_000277.1(PAH):c.609C>T (p.Cys203=)

CA229649

102756 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2152f218-f763-4b21-bdc6-6f57d1ed1c05

HGVS expressions

NM_000277.1:c.609C>T

NM_000277.1(PAH):c.609C>T (p.Cys203=)

NM_000277.2:c.609C>T

NM_001354304.1:c.609C>T

NM_000277.3:c.609C>T

NM_001354304.2:c.609C>T

ENST00000307000.7:c.594C>T

ENST00000549111.5:n.705C>T

ENST00000553106.5:c.609C>T

NC_000012.12:g.102855233G>A

CM000674.2:g.102855233G>A

NC_000012.11:g.103249011G>A

CM000674.1:g.103249011G>A

NC_000012.10:g.101773141G>A

NG_008690.1:g.67370C>T

NG_008690.2:g.108178C>T

Uncertain Significance

BS1

PP3

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.609C>T (p.Cys203=) variant in PAH has not been reported in a patient with PAH deficiency to our knowledge. This variant has a MAF that is too high (0.00473 in gnomAD). A deleterious effect is predicted using HSF, IIEs from Zhang et al, Fas-ESS hexamers, and NNSplice, but Splice AI predicts a benign effect (0). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: BS1.

BS1

MAF = 0.00473 in GnomAD, 1 homozygote in ExAC

PP3

HSF: Activation of an exonic cryptic donor site (New site +70.13). Potential alteration of splicing. IIEs from Zhang et al and Fas-ESS hexamers: Creation of an exonic ESS site. Potential alteration of splicing. NNSplice: Acc increased wt: 0.79 / mu: 0.89; Splice AI Benign (0); TraP Score 0.12 (~75th%ile)

Approved on: 2020-10-23

Published on: 2020-10-23

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