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>A

CA229453

102605 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: f91cc9c6-b8c8-4183-a8c9-a7f0c30fd1ba

Approved on: 2019-05-26

Published on: 2019-05-26

HGVS expressions

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

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

NC_000012.12:g.102912786C>T

CM000674.2:g.102912786C>T

NC_000012.11:g.103306564C>T

CM000674.1:g.103306564C>T

NC_000012.10:g.101830694C>T

NG_008690.1:g.9817G>A

NG_008690.2:g.50625G>A

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

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

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

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

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

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

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

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

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

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

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

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

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

Likely Pathogenic

PM3_Strong PP4_Moderate PP3 PM2

Evidence Links 3

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.168+5G>A variant has been identified in at least 4 probands with phenotypes ranging from mild HPA to classic PKU, with at least 2 probands excluding BH4 deficiency (PMIDs: 9429153, 26413448, 27121329). It has been detected in the homozygous form (PMID: 26413448) as well as in trans with pathogenic variants R297H (PMID: 9429153), I65T, and S349P (PMID: 27121329). 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 likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3.

PM3_Strong

c.168+5G>A has been observed in trans with R297H (ClinVar 92750, Pathogenic), I65T (ClinVar 636, Pathogenic), and S349P (ClinVar 615, Pathogenic/Likely Pathogenic), and once in the homozygous state.

c.168+5G>A was observed in the homozygous state in one proband. PubMed:26413448

c.168+5G>A has been observed in trans with R297H (ClinVar 92750, Pathogenic). PubMed:9429153

Two probands were compound heterozygous for c.168+5G>A and either I65T (ClinVar 636, Pathogenic) or S349P (ClinVar 615, Pathogenic/Likely Pathogenic). PubMed:27121329

PP4_Moderate

Four probands have been described with this variant ranging from mild HPA to classic PKU, in two of these probands BH4 deficiency was ruled out.

One homozygous proband with c.168+5G>A had classical PKU with (PHE > 1200 umol/L). No reported testing to rule out BH4 deficiency. PubMed:26413448

One proband compound heterozygote with c.168G>A had mild HPA (PHE 363 umol/L). No reported testing to rule out BH4 deficiency. PubMed:9429153

Two compound heterozygotes carrying c.168G>A were described. One with I65T and mild HPA (360-600 umol/L PHE) and one with classic PKU (>1200 umol/L PHE). BH4 deficiency was ruled out. PubMed:27121329

PP3

HSF (-13.06%) and MaxEnt (-71.04%) agree that there is alteration of the WT donor site, most probably affecting splicing.

PM2

Absent from 1000G, ESP, and gnomAD.

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