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.632delC (p.Pro211Hisfs)

CA229667

102767 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 206011ac-8bc7-4dfb-abbb-bbe17ef66221

HGVS expressions

NM_000277.2:c.632delC

NM_000277.2(PAH):c.632delC (p.Pro211Hisfs)

NC_000012.12:g.102855211del

CM000674.2:g.102855211del

NC_000012.11:g.103248989del

CM000674.1:g.103248989del

NC_000012.10:g.101773119del

NG_008690.1:g.67393del

NG_008690.2:g.108201del

NM_000277.1:c.632del

NM_000277.2:c.632del

NM_001354304.1:c.632del

NM_000277.3:c.632del

ENST00000307000.7:c.617del

ENST00000549111.5:n.728del

ENST00000553106.5:c.632del

Pathogenic

PVS1 PP4 PM3 PM2

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.632delC (p.Pro211Hisfs) variant in PAH leads to a frameshift at amino acid 211/432. It is identified with low frequency in population databases (1.648e-5). It has been identified in two individuals with Phenylketonuria as a homozygous variant and in trans with c.1066-11G>A (PMID: 26413448; 26666653). It has been described in multiple patients with PKU, although a defect in BH4 metabolism has not been excluded as a cause of elevated phenylalanine in any case. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.

PVS1

single bp deletion resulting in frameshift at aa 211/453.

PP4

Described in multiple independent patients, all with classic PKU (Phe >1200umol/L), BH4 defect not specifically excluded in any pub. (Guldberg, 1996; PMID: 26413448; PMID: 26666653; Sarkissian, 2011)

Single patient PubMed:26666653

single homozygous patient with classic PKU PubMed:26413448

PM3

Homozygous (Bilgiari, 2015) and in trans with 1066-11G>A (pathogenic, Jeannesson-Thivisol, 2015)

in trans PubMed:26666653

single patient described with classic PKU PubMed:26413448

PM2

Found 2 times in gnomAD (0.000008127) and 2 times in ExAC (1.648e-05)

Approved on: 2018-12-09

Published on: 2019-08-17

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