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.168G>T (p.Glu56Asp)

CA229459

102610 (ClinVar)

Gene: PAH

Condition: phenylketonuria

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 5d55702e-1dc3-4256-8539-e31f1b076a73

HGVS expressions

NM_000277.2:c.168G>T

NM_000277.2(PAH):c.168G>T (p.Glu56Asp)

NC_000012.12:g.102912791C>A

CM000674.2:g.102912791C>A

NC_000012.11:g.103306569C>A

CM000674.1:g.103306569C>A

NC_000012.10:g.101830699C>A

NG_008690.1:g.9812G>T

NG_008690.2:g.50620G>T

ENST00000553106.6:c.168G>T

ENST00000307000.7:c.153G>T

ENST00000546844.1:c.168G>T

ENST00000548677.2:n.255G>T

ENST00000548928.1:n.90G>T

ENST00000549111.5:n.264G>T

ENST00000550978.6:n.152G>T

ENST00000551337.5:c.168G>T

ENST00000551988.5:n.257G>T

ENST00000553106.5:c.168G>T

ENST00000635500.1:n.136G>T

NM_000277.1:c.168G>T

NM_001354304.1:c.168G>T

NM_000277.3:c.168G>T

NM_001354304.2:c.168G>T

Pathogenic

PM3_Very Strong PM2 PP4_Moderate

PP3 PM5

Evidence Links 1

Expert Panel

Phenylketonuria VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Phenylketonuria VCEP

The c.168G>T (p.Glu56Asp) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded) (PMID: 21147011, 23932990, 30050108). This variant is absent in population databases. This variant was detected with multiple pathogenic variants: R243Q (PMID: 8019568); R408W and T356X (PMID: 21147011); p.V399V, c.442-1G>A, p.I65T, p.R261Q (PMID: 30050108). Computational prediction tools and conservation analysis do not agree on the impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate.

PM3_Very Strong

E56D detected with: R243Q (maternally inh, P, 11 submitters) PMID: 8019568; R408W and T356X, both pathogenic in ClinVar. Parental analysis not reported. PMID: 21147011; p.V399V (P 5 submitters), c.442-1G>A (P 4 submitters), p.I65T (P 11 submitters), p.R261Q (P 11 submitters). PMID: 30050108 The validation tests on parents were performed. 6 pts

E56D seen in trans with p.Y356X in 1 patient, and p.R408W (VarID 577, Pathogenic) in another patient PubMed:21147011

PM2

Absent from ExAC, gnomAD, 1000G, ESP

PP4_Moderate

E56D found on 2 alleles in 2 patients with classic PKU. BH4 deficiency excluded: Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). PMID: 21147011; Found in 1 Chinese patient with PAH deficiency, A defect in the synthesis or recycling of tetrahydrobiopterin was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes. PMID: 23932990

588 hyperphenylalaninemic patients were investigated. Assessment included PAH gene and genes of the BH4 synthesis/recycling pathways (PTS and QDPR). E56D found on 2 alleles in 2 patients, both with classic PKU. PubMed:21147011

PP3

Conflicting predictions of pathogenicity: Benign in Polyphen2, deleterious in SIFT and MutationTaster

PM5

The current variant is the only variant found in this codon in ClinVar

Approved on: 2020-06-29

Published on: 2021-07-09

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