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]

Variant: NM_000277.2(PAH):c.1315+1G>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA251522

576 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a0e84b26-03d1-42c0-a937-859d45d287e0

Approved on: 2018-08-05

Published on: 2019-08-17

HGVS expressions

NM_000277.2:c.1315+1G>A

NM_000277.2(PAH):c.1315+1G>A

NC_000012.12:g.102840399C>T

CM000674.2:g.102840399C>T

NC_000012.11:g.103234177C>T

CM000674.1:g.103234177C>T

NC_000012.10:g.101758307C>T

NG_008690.1:g.82204G>A

NG_008690.2:g.123012G>A

NM_000277.1:c.1315+1G>A

NM_001354304.1:c.1315+1G>A

NM_000277.3:c.1315+1G>A

ENST00000307000.7:c.1300+1G>A

ENST00000551114.2:n.977+1G>A

ENST00000553106.5:c.1315+1G>A

ENST00000635477.1:n.419+1G>A

ENST00000635528.1:n.830+1G>A

Pathogenic

PP4_Moderate PVS1 PS3 PM3

Evidence Links 4

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

PAH-specific ACMG/AMP criteria applied: PS3: abolishes PAH activity due to protein instability (PMID:17935162; PMID:3615198); PM3: (PMID:24941924); PP4_Moderate: Reported in Galician PAH deficiency population. BH4 deficiency ruled out. (PMID:23500595); PVS1: Canonical +1 splice site. In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM3, PP4_Moderate, PVS1).

PP4_Moderate

Reported in Galician PAH deficiency population. BH4 deficiency ruled out.

Reported IVS12+1G>A in a Galician population of hyperphenylalaninemia (HPA) patients with a frequency of 1%. Variant was listed in Table 1 associated with <1% residual PAH enzyme activity compared to normal; BH4 deficiency ruled out PubMed:23500595

PVS1

Canonical +1 splice site

PS3

abolishes PAH activity due to protein instability

Reported IVS12+1G>A in a study of 315 patients from the BIOPKUdb. Variant was listed as a BH4-nonresponsive mutation with no residual PAH enzyme activity. PubMed:17935162

Identified IVS12+1G>A (described as GT>AT in intron 12) in a PAH cDNA clone isolated from a cDNA library generated from a phenylketonuria (PKU) carrier individual. Expression of this cDNA clone into COS cells results in the deletion of exon 12 and abolishes PAH activity due to protein instability. PubMed:3615198

PM3

In trans with a LOF allele; Table 2 Observed phenotype_Classic PKU PubMed:24941924

Curation History

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