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.1161C>T (p.Tyr387=)

CA6748733

703089 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 965cc26c-6464-4bdf-a47e-5ba989913277

HGVS expressions

NM_000277.3:c.1161C>T

NM_000277.3(PAH):c.1161C>T (p.Tyr387=)

NC_000012.12:g.102843684G>A

CM000674.2:g.102843684G>A

NC_000012.11:g.103237462G>A

CM000674.1:g.103237462G>A

NC_000012.10:g.101761592G>A

NG_008690.1:g.78919C>T

NG_008690.2:g.119727C>T

ENST00000553106.6:c.1161C>T

ENST00000307000.7:c.1146C>T

ENST00000549247.6:n.920C>T

ENST00000551114.2:n.823C>T

ENST00000553106.5:c.1161C>T

ENST00000635477.1:n.265C>T

ENST00000635528.1:n.676C>T

NM_000277.1:c.1161C>T

NM_000277.2:c.1161C>T

NM_001354304.1:c.1161C>T

NM_001354304.2:c.1161C>T

Uncertain Significance

BP7

BS1

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1161C>T (p.Tyr387=) variant in PAH has not been reported in the literature to our knowledge. It is a silent variant with no splice impact predicted. It is present at low frequencies in population databases (MAF 0.00024 in gnomAd and ExAc, 0 homozygotes) which is above our threshold for PM2 (<0.0002) but below our threshold for BS1 (>0.002). Therefore, it meets criteria to be classified as uncertain significance. PAH-specific ACMG/AMP criteria applied: BP7.

BP7

Per HSF, there is no significant impact on splicing signals predicted. SpliceAI predicts donor loss with a score of 0.11, and no predicted impact. The TraP score is 0.001

BS1

MAF=0.00144. Present at low frequencies in population databases (MAF 0.00024 in gnomAd and ExAc, MAF 0.00046 in ESP). Spoke to Invitae and their reasoning for benign classification was that the ExAc data met their threshold for benign. Although their internal data was not used for evaluation, they have seen this 50+ times in their carrier screening

Approved on: 2021-09-26

Published on: 2021-11-21

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