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.1200-1G>A

CA220577

92730 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3ef13555-39cd-454f-bafb-aa98f5ede6c9

HGVS expressions

NM_000277.3:c.1200-1G>A

NM_000277.3(PAH):c.1200-1G>A

NM_000277.1:c.1200-1G>A

NM_000277.2:c.1200-1G>A

NM_001354304.1:c.1200-1G>A

NM_001354304.2:c.1200-1G>A

ENST00000307000.7:c.1185-1G>A

ENST00000549247.6:n.959-1G>A

ENST00000551114.2:n.862-1G>A

ENST00000553106.5:c.1200-1G>A

ENST00000635477.1:n.304-1G>A

ENST00000635528.1:n.715-1G>A

NC_000012.12:g.102840516C>T

CM000674.2:g.102840516C>T

NC_000012.11:g.103234294C>T

CM000674.1:g.103234294C>T

NC_000012.10:g.101758424C>T

NG_008690.1:g.82087G>A

NG_008690.2:g.122895G>A

Pathogenic

PM2 PM3 PVS1 PP4

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

This c.1200-1G>A variant in PAH was reported in 2 Caucasian patients with PAH deficiency (PMID: 23430918) detected with pathogenic variants p.Phe55Leu and c.1315+1G>A. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. This variant in the -1 splice acceptor site results in exon skipping, which disrupts the reading frame and is predicted to undergo nonsense mediated decay. The exon is present in biologically-relevant transcripts. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.

PM2

PM2_met: This variant is absent from population databases gnomAD and ExAC.

PM3

PM3_met: This variant was detected with pathogenic variants in 2 patients with PAH deficiency (PMID: 23430918). 23430918 - This variant was detected in trans with the pathogenic PAH variant p.Phe55Leu in 1 Caucasian patient with PAH deficiency. This variant was detected in trans with the pathogenic PAH variant c.1315+1G>A in 1 Caucasian patient with PAH deficiency. Parental analysis was not performed to confirm compound heterozygosity.

PVS1

PVS1_met: This variant in the -1 splice acceptor site of IVS11 results in exon skipping or use of a cryptic splice site. The variant disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. This variant breaks the splice site in IVS11 according to Splice AI (0.95 - splice-altering) and TraP (0.581, >99%ile, probably damaging).

PP4

PP4_met: This variant was documented in 2 patients with PAH deficiency (PMID: 23430918). 23430918, Sarkissian - This variant was documented in 2 Caucasian patients with PAH deficiency. All PKU patients included in this study had phenylalanine plasma concentrations >120 μM as described in the clinical trial protocols. A defect in BH4 metabolism was not excluded through a BH4 loading test, urinary pterin analysis and DHPR activity assay.

PubMed:23430918

Approved on: 2020-10-15

Published on: 2020-10-15

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