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.346_347del (p.Asp116fs)

CA915946683

635217 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bc07013c-3216-493b-a530-39c2884f328a

HGVS expressions

NM_000277.3:c.346_347delGA

NM_000277.3:c.346_347del

NM_000277.3(PAH):c.346_347del (p.Asp116fs)

NM_000277.1:c.346_347del

NM_000277.2:c.346_347del

NM_001354304.1:c.346_347del

NM_001354304.2:c.346_347del

ENST00000307000.7:c.331_332del

ENST00000546844.1:c.346_347del

ENST00000548928.1:n.268_269del

ENST00000549111.5:n.442_443del

ENST00000550978.6:n.330_331del

ENST00000551337.5:c.346_347del

ENST00000551988.5:n.435_436del

ENST00000553106.5:c.346_347del

NC_000012.12:g.102894741_102894742del

CM000674.2:g.102894741_102894742del

NC_000012.11:g.103288519_103288520del

CM000674.1:g.103288519_103288520del

NC_000012.10:g.101812649_101812650del

NG_008690.1:g.27862_27863del

NG_008690.2:g.68670_68671del

Pathogenic

PP4_Moderate PM2 PM3 PVS1

Evidence Links 0

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.346_347del (p.Asp116fs) variant in PAH is a null variant (frameshift variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It has been previously reported in an Ugyur proband (PMID: 31355225) with mild PKU; BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). The patient was compound heterozygous for the variant (confirmed by parental testing) and carried it in trans with the p.E390G variant (Likely Pathogenic per ClinGen PAH working group) (PM3). It is also reported pathogenic in Clinvar (ID 635217) by one lab, in a case with PKU; no further information is given.

PP4_Moderate

It has been previously reported in an Ugyur proband (PMID: 31355225) with mild PKU; BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate).

PM2

It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).

PM3

It has been previously reported in an Ugyur proband (PMID: 31355225) with mild PKU; BH4 deficiency was formally excluded by urinary pterin analysis (PP4_Moderate). The patient was compound heterozygous for the variant (confirmed by parental testing) and carried it in trans with the p.E390G variant (Likely Pathogenic per ClinGen PAH working group) (PM3).

PVS1

The c.346_347del (p.Asp116fs) variant in PAH is a null variant (frameshift variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1).

Approved on: 2020-04-16

Published on: 2020-04-16

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