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.904delT (p.Ser303Profs)

CA229840

102888 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 4208842e-4249-4edb-b2a1-f7e4c5e271f7

HGVS expressions

NM_000277.2(PAH):c.904delT (p.Ser303Profs)

NC_000012.12:g.102851695del

CM000674.2:g.102851695del

NC_000012.11:g.103245473del

CM000674.1:g.103245473del

NC_000012.10:g.101769603del

NG_008690.1:g.70911del

NG_008690.2:g.111719del

NM_000277.1:c.907del

NM_000277.2:c.907del

NM_001354304.1:c.907del

NM_000277.3:c.907del

ENST00000307000.7:c.892del

ENST00000549247.6:n.666del

ENST00000551114.2:n.569del

ENST00000553106.5:c.907del

ENST00000635477.1:n.68del

Pathogenic

PVS1 PP4 PM2 PM3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.904delT (p.Ser303Profs*38) variant in PAH has been observed in at least one patient with classic PKU (plasma phenylalanine greater than 1200 micromolar) with a known pathogenic variant p.Ser70del (PMID:16256386). This variant is absent in population databases including: 1000 Genomes, ESP, and extremely low in gnomAD. This is a single base pair deletion that creates a frameshift in exon 9 and is predicted to undergo nonsense mediated decay with the truncated region critical to protein function. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.

PVS1

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

PP4

Observed in a patient with classical PKU (BH4 deficiency not ruled out). PMID: 16256386

Observed in a patient with classical PKU (BH4 deficiency not ruled out. Phe > 1200uM) (Table 1 + 2). PMID: 16256386 PubMed:16256386

PM2

1 gnomAD (genomes)

PM3

Observed with S70del (Pathogenic in ClinVar). PMID: 16256386

Observed with S70del (Table 2). Maternal or paternal inheritance of mutations was determined particularly for patients with novel mutation when parental DNA was available. PubMed:16256386

Approved on: 2019-04-04

Published on: 2019-08-16

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