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+5G>T

CA229455

102607 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 702a4760-78ba-4d90-aadc-14a51736cea0

HGVS expressions

NM_000277.2:c.168+5G>T

NM_000277.2(PAH):c.168+5G>T

NC_000012.12:g.102912786C>A

CM000674.2:g.102912786C>A

NC_000012.11:g.103306564C>A

CM000674.1:g.103306564C>A

NC_000012.10:g.101830694C>A

NG_008690.1:g.9817G>T

NG_008690.2:g.50625G>T

NM_000277.1:c.168+5G>T

NM_001354304.1:c.168+5G>T

NM_000277.3:c.168+5G>T

ENST00000307000.7:c.153+5G>T

ENST00000546844.1:c.168+5G>T

ENST00000548677.2:n.255+5G>T

ENST00000548928.1:n.90+5G>T

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

ENST00000550978.6:n.152+5G>T

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

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

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

ENST00000635500.1:n.136+5G>T

Uncertain Significance

PM2 PP4_Moderate PP3

PM3

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+5G>T variant has been identified in at least 2 probands, with at least 1 classic PKU proband excluding BH4 deficiency (PMIDs: 30747360). This variant is absent from 1000G, ESP, and gnomAD databases. Computational analysis predicts an alteration of the WT donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as unknown significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3.

PM2

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

PP4_Moderate

One c.168+5G>T allele was identified in a Classic PKU case (Phe ≥ 1200 μmol/L) with tetrahydrobiopterin deficiency excluded through a BH4 loading test, a urinary pterin analysis, and a DHPR activity assay on DBS samples.

PP3

HSF (-13.22%) and MaxEnt (-57.01%) agree that there is alteration of the WT donor site, most probably affecting splicing.

PM3

This variant has been reported in two compound heterozygous probands (PMIDs: 8406445 and 30747360) however the second allele was not specified.

Approved on: 2019-08-25

Published on: 2019-08-25

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