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_000277.2(PAH):c.168+6T>G

CA229456

102608 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f2c089c9-4bde-4fe4-8e84-06d07ad9e9a5

HGVS expressions

NM_000277.2:c.168+6T>G

NM_000277.2(PAH):c.168+6T>G

NC_000012.12:g.102912785A>C

CM000674.2:g.102912785A>C

NC_000012.11:g.103306563A>C

CM000674.1:g.103306563A>C

NC_000012.10:g.101830693A>C

NG_008690.1:g.9818T>G

NG_008690.2:g.50626T>G

NM_000277.1:c.168+6T>G

NM_001354304.1:c.168+6T>G

NM_000277.3:c.168+6T>G

ENST00000307000.7:c.153+6T>G

ENST00000546844.1:c.168+6T>G

ENST00000548677.2:n.255+6T>G

ENST00000548928.1:n.90+6T>G

ENST00000549111.5:n.264+6T>G

ENST00000550978.6:n.152+6T>G

ENST00000551337.5:c.168+6T>G

ENST00000551988.5:n.257+6T>G

ENST00000553106.5:c.168+6T>G

ENST00000635500.1:n.136+6T>G

Uncertain Significance

PP4 PM2 PM3_Supporting

PP3

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.168+6T>G variant has been identified in at least 1 proband with classical PKU (PMIDs: 8889590) in trans with pathogenic variant c.47_48delCT (ClinVar 102696). This variant is absent from 1000G, ESP, and gnomAD databases. In summary, this variant meets criteria to be classified as unknown significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3_supporting, PP4.

PP4

One patient with classical PKU is described with this variant

One patient is described with this variant however phenotypic details are not provided, only that the patient was diagnosed with classical PKU (no PHE levels provided). Diagnosis and classification of PAH deficiency were based on the criteria described by Guttler (1980). PubMed:8889590

PM2

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

PM3_Supporting

One patient has been described as compound heterozygous for the c.168+6T>G and c.47_48delCT (ClinVar 102696, Pathogenic) variants.

One patient was described as compound heterozygous for the c.168+6T>G and c.47_48delCT (ClinVar 102696, Pathogenic) variants. Parental confirmation not reported. PubMed:8889590

PP3

There is not consensus among splicing predictors as to the effect of this variant, MaxEntScan predicts alteration of the WT donor site, most probably affecting splicing, however HSF and NNSPLICE do not.

Approved on: 2019-09-29

Published on: 2019-10-02

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