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]

Variant: NM_000277.2(PAH):c.169_171delGAG (p.Glu57del)

CA229461

102613 (ClinVar)

Gene: PAH (HGNC:5053)

Condition: phenylketonuria (MONDO:0009861)

Inheritance Mode: Autosomal recessive inheritance

UUID: 322ad14d-14cd-4966-a70d-b6f5fb632418

Approved on: 2019-08-26

Published on: 2019-08-26

HGVS expressions

NM_000277.2(PAH):c.169_171delGAG (p.Glu57del)

NM_000277.2:c.169_171del

NC_000012.12:g.102894918_102894920del

CM000674.2:g.102894918_102894920del

NC_000012.11:g.103288696_103288698del

CM000674.1:g.103288696_103288698del

NC_000012.10:g.101812826_101812828del

NG_008690.1:g.27685_27687del

NG_008690.2:g.68493_68495del

NM_000277.1:c.169_171del

NM_001354304.1:c.169_171del

NM_000277.3:c.169_171del

ENST00000307000.7:c.154_156del

ENST00000546844.1:c.169_171del

ENST00000548677.2:n.256_258del

ENST00000548928.1:n.91_93del

ENST00000549111.5:n.265_267del

ENST00000550978.6:n.153_155del

ENST00000551337.5:c.169_171del

ENST00000551988.5:n.258_260del

ENST00000553106.5:c.169_171del

ENST00000635500.1:n.137_139del

Likely Pathogenic

PP4 PM2 PM4 PM3_Strong

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.169_171del in-frame deletion variant has been identified in at least 2 probands with phenotypes of mild to classic PKU (PMIDs: 18299955, 22106832). It has been detected in trans with pathogenic variants Ala403Val (PMID: 18299955) and c.1066-11G>A (PMID: 22106832). This variant is absent from 1000G, ESP, and gnomAD databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PM4, PP4.

PP4

One proband has been described with PHE levels of 6.5–10 mg/dl. It was unclear if a defect of BH4 cofactor metabolism was excluded.

A mild PKU patient is reported to be heterozygous for this variant and Ala403Val (ClinVar 92731, Pathogenic). Mild PKU was defined as having plasma phenylalanine concentrations of 6.5–10 mg/dl. Most patients were tested for the exclusion of lacking the cofactor BH4 but it was not specified if that included this patient. PubMed:18299955

PHE levels were not provided for the compound heterozygous patient described with this c.169_171del variant and the c.1066-11G>A . PubMed:22106832

PM2

This variant is absent from gnomAD, ExAC, 1000 Genomes, and ESP.

PM4

The in-frame deletion removes one amino acid (Glu57).

PM3_Strong

This variant has been reported in two compound heterozygotes, in trans with Ala403Val (ClinVar 92731, Pathogenic) and c.1066-11G>A (ClinVar 607, Pathogenic).

A mild PKU patient is reported to be heterozygous for this variant and Ala403Val (ClinVar 92731, Pathogenic). This c.169_171del variant is referred to as "IVS2 - 2 del" in this article but this is in fact the intended variant as this paper is the reference provided in BIOPKU and HGMD has confirmed, by personal communication with the authors, that this is the c.169_171del variant. PubMed:18299955

A compound heterozygous patient is described with this c.169_171del variant and the c.1066-11G>A (ClinVar 607, Pathogenic) variant. PubMed:22106832

Curation History

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