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.168G>A (p.Glu56=)

CA229457

102609 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 2be16bc3-2015-45e9-b854-cbb09e3aa99b

Approved on: 2019-11-10

Published on: 2020-01-25

HGVS expressions

NM_000277.2:c.168G>A

NM_000277.2(PAH):c.168G>A (p.Glu56=)

NM_000277.1:c.168G>A

NM_001354304.1:c.168G>A

NM_000277.3:c.168G>A

NM_001354304.2:c.168G>A

ENST00000307000.7:c.153G>A

ENST00000546844.1:c.168G>A

ENST00000548677.2:n.255G>A

ENST00000548928.1:n.90G>A

ENST00000549111.5:n.264G>A

ENST00000550978.6:n.152G>A

ENST00000551337.5:c.168G>A

ENST00000551988.5:n.257G>A

ENST00000553106.5:c.168G>A

ENST00000635500.1:n.136G>A

NC_000012.12:g.102912791C>T

CM000674.2:g.102912791C>T

NC_000012.11:g.103306569C>T

CM000674.1:g.103306569C>T

NC_000012.10:g.101830699C>T

NG_008690.1:g.9812G>A

NG_008690.2:g.50620G>A

Uncertain Significance

PP3 PM2 BP2 BS2

PP4 PM5 BP7

Evidence Links 2

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.168G>A (p.Glu56=) variant in PAH has been reported as a polymoprhism. It was found in Arab patients’ DNA, including patients and controls (zygosity not reported). (BS2; PMID: 18299955) However, this variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). While it is a synonymous variant, alteration of the WT donor site affecting splicing is suggested by Human Splicing Finder and Alamut (PP3). It was observed in cis with a pathogenic variant, IVS2+1G>A (BP2; PMID: 24368688). In summary, this variant meets criteria to be classified as uncertain significance for PAH due to conflicting evidence. ACMG/AMP criteria applied: BS2, BP2, PM2, PP3.

PP3

HSF: Alteration of the WT donor site, most probably affecting splicing. Alamut: Reduces/eliminates splicing at donor site. (-.78 reduction).

PM2

Absent from ExAC, gnomAD, 1000G, ESP

BP2

Observed in cis with IVS2+1G>A (LP in ClinVar) PMID: 24368688

c.168G>A (p.E56E), in cis with IVS2+1G>A (VarID 102604, Likely Pathogenic PubMed:24368688

BS2

The E56E SNP was found in Arab patients’ DNA, including patients and controls. PMID: 18299955. (zygosity not reported)

The E56E SNP was found in Arab patients’ DNA (13.8%), including patients and controls. PMID: 18299955. PubMed:18299955

PP4

The E56E SNP was found in Arab patients’ DNA (13.8%), including patients and controls. PMID: 18299955.

One hundred and eleven patients, including seven families with two or more affected individuals, were recruited from the records of the NSW Newborn Screening Programme or from the PKU Clinic at the Children’s Hospital at Westmead, Sydney Australia. Ten polymorphisms were identified in the cohort, with nine having been previously reported: c.168G>A (p.E56E, in cis with IVS2+1G>A). Further details not provided. PubMed:24368688

By using PCR/dHPLC and DNA sequencing, we screened all exons of the PAH gene in 180 unrelated patients with four different PKU phenotypes. Eight common polymorphic DNA alterations (SNPs) at different frequencies were detected in patients from all ethnic groups and controls group, including E56E. The E56E SNP was only found in Arab patients’ DNA (13.8%). PubMed:18299955

PM5

E56D, no assertion provided

BP7

HSF: Alteration of the WT donor site, most probably affecting splicing. Alamut: Reduces/eliminates splicing at donor site. (-.78 reduction)

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