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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000277.2(PAH):c.137delG (p.Gly46Valfs)

CA229440

102597 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6a118ab0-2285-490f-8ce5-c42461c2f250

HGVS expressions

NM_000277.2(PAH):c.137delG (p.Gly46Valfs)

NC_000012.12:g.102912823del

CM000674.2:g.102912823del

NC_000012.11:g.103306601del

CM000674.1:g.103306601del

NC_000012.10:g.101830731del

NG_008690.1:g.9781del

NG_008690.2:g.50589del

NM_000277.1:c.137del

NM_000277.2:c.137del

NM_001354304.1:c.137del

NM_000277.3:c.137del

ENST00000307000.7:c.122del

ENST00000546844.1:c.137del

ENST00000548677.2:n.224del

ENST00000548928.1:n.59del

ENST00000549111.5:n.233del

ENST00000550978.6:n.121del

ENST00000551337.5:c.137del

ENST00000551988.5:n.226del

ENST00000553106.5:c.137del

ENST00000635500.1:n.105del

Pathogenic

PVS1 PP4 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.137delG (p.Gly46Vfs*15) is a frameshift in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in 1 individual with PKU (BH4 deficiency not excluded), who carried a second splicing variant (PP4; PMID: 10196714 ). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4.

PVS1

Frameshift mutation in exon 2 of 13, predicted to undergo nonsense mediated decay with the truncated region critical to protein function

PP4

Variant observed in 1 patient who carried a second splicing mutation. See table 2, family C, IVS2nt, which is the same as "IVS 2nt5g-c" described in the paper. It's not clear what is the splicing variant; however either c.168+5G>C, or c.60+5G>C, the likely candidates, are disrupting splicing at the donor site. PubMed:10196714

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2019-04-03

Published on: 2019-08-16

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