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.1065+3A>G

CA212751

633 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 1eaf05e7-3220-43e3-be9a-82f4eb06577c

HGVS expressions

NM_000277.2:c.1065+3A>G

NM_000277.2(PAH):c.1065+3A>G

NC_000012.12:g.102844333T>C

CM000674.2:g.102844333T>C

NC_000012.11:g.103238111T>C

CM000674.1:g.103238111T>C

NC_000012.10:g.101762241T>C

NG_008690.1:g.78270A>G

NG_008690.2:g.119078A>G

NM_000277.1:c.1065+3A>G

NM_001354304.1:c.1065+3A>G

NM_000277.3:c.1065+3A>G

ENST00000307000.7:c.1050+3A>G

ENST00000549247.6:n.824+3A>G

ENST00000551114.2:n.727+3A>G

ENST00000553106.5:c.1065+3A>G

ENST00000635477.1:n.169+3A>G

ENST00000635528.1:n.580+3A>G

Likely Pathogenic

PP3 PP4 PP1 PM3 PM2

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.1065+3A>G variant in PAH was detected in 2 siblings with an increased serum Phenylalanine level of 365 uM. BH4 deficiency was not assessed/reported. (PMID: 8088845) They were compound heterozygous for Y414C. The c.1065+3A>G variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted for this variant in HSF and MaxEnt (Alteration of the WT donor site; activation of an intronic cryptic donor site). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP1, PP3, PP4.

PP3

Deleterious effect predicted in HSF and MaxEnt: Alteration of the WT donor site, Activation of an intronic cryptic donor site.

PP4

Detected in 2 siblings with serum Phe of 365 uM. BH4 deficiency not assessed. ( PMID: 8088845)

Detected in 2 siblings (patients R and S) with medium serum Phe of 365 uM. BH4 cofactor assessment not stated. PubMed:8088845

PP1

Detected in 2 siblings with elevated serum Phe of 365 (PMID: 8088845)

Detected in 2 siblings with elevated serum Phe of 365 PubMed:8088845

PM3

2 siblings compound heterozygous for Y414C ( PMID: 8088845)

2 siblings compound heterozygous for Y414C (Pathogenic in ClinVar) PubMed:8088845

PM2

Absent from ExAC, gnomAD, 1000G, ESP

Approved on: 2018-12-10

Published on: 2019-05-04

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