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.168_168+1delGGinsAA

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA273936

188771 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: bba6e7f2-881f-422d-8e2c-72d0cf8a7c1d

Approved on: 2019-08-25

Published on: 2019-08-25

HGVS expressions

NM_000277.2:c.168_168+1delGGinsAA

NM_000277.2(PAH):c.168_168+1delGGinsAA

NM_000277.1:c.168_168+1delinsAA

NM_000277.2:c.168_168+1delinsAA

NM_001354304.1:c.168_168+1delinsAA

NM_000277.3:c.168_168+1delinsAA

NM_001354304.2:c.168_168+1delinsAA

ENST00000307000.7:c.153_153+1delinsAA

ENST00000546844.1:c.168_168+1delinsAA

ENST00000548677.2:n.255_255+1delinsAA

ENST00000548928.1:n.90_90+1delinsAA

ENST00000549111.5:n.264_264+1delinsAA

ENST00000550978.6:n.152_152+1delinsAA

ENST00000551337.5:c.168_168+1delinsAA

ENST00000551988.5:n.257_257+1delinsAA

ENST00000553106.5:c.168_168+1delinsAA

ENST00000635500.1:n.136_136+1delinsAA

NC_000012.12:g.102912790_102912791delinsTT

CM000674.2:g.102912790_102912791delinsTT

NC_000012.11:g.103306568_103306569delinsTT

CM000674.1:g.103306568_103306569delinsTT

NC_000012.10:g.101830698_101830699delinsTT

NG_008690.1:g.9812_9813delinsAA

NG_008690.2:g.50620_50621delinsAA

Likely Pathogenic

PP4 PM2 PVS1_Moderate 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.168_168+1delGGinsAA variant has been identified in at least 6 probands with classic PKU (PMIDs: 1301942, 8825928). It has been detected in the homozygous form (PMID: 1301942) as well as in trans with the pathogenic variant R408W (PMID: 8825928). This variant is absent from 1000G, ESP, and gnomAD databases. This variant results in a broken donor splice site, expected to result in the in-frame deletion of exon 2. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PVS1_Moderate, PM2, PP4.

PP4

Several homozygous probands have been described with Classical PKU and PHE levels >=1.2mM. A defect of BH4 cofactor metabolism was not excluded.

Patients 1 through 5 (all identified as homozygous for this variant) were each described with Classical PKU having PHE levels >=1.2mM (range: 1.21-2.53). PubMed:1301942

PM2

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

PVS1_Moderate

The altered +1 donor splice site is expected to result in the skipping of exon 2, a deletion of 36 amino acids (8% of the protein) with retention of the reading frame.

PM3_Strong

This variant has been reported in trans with the Arg408Trp (ClinVar 577, Pathogenic) as well as in 5 homozygous individuals.

Patients 1 through 5 were all identified as homozygous for this variant. PubMed:1301942

Patient LGL5044 was identified as compound heterozygous for this variant and Arg408Trp (ClinVar 577, Pathogenic). PubMed:8825928

Curation History

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