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.168_168+1delGGinsAA

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

PVS1_Moderate PP4 PM2 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.

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.

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.

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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.