NM_000277.3(PAH):c.169G>T (p.Glu57Ter) AND Phenylketonuria

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 29, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000106349.3

Allele description [Variation Report for NM_000277.3(PAH):c.169G>T (p.Glu57Ter)]

NM_000277.3(PAH):c.169G>T (p.Glu57Ter)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.169G>T (p.Glu57Ter)

HGVS:

NC_000012.12:g.102894918C>A
NG_008690.2:g.68493G>T
NM_000277.3:c.169G>TMANE SELECT
NM_001354304.2:c.169G>T
NP_000268.1:p.Glu57Ter
NP_001341233.1:p.Glu57Ter
NC_000012.11:g.103288696C>A
NM_000277.1:c.169G>T
NM_000277.2(PAH):c.169G>T
p.Glu57Ter

Protein change:

E57*

Links:

dbSNP: rs140945592

NCBI 1000 Genomes Browser:

rs140945592

Molecular consequence:

NM_000277.3:c.169G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354304.2:c.169G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000143848	Inserm U 954, Faculté de Médecine de Nancy	no assertion criteria provided	probable-pathogenic	unknown	not provided
SCV001146717	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Sep 29, 2019)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000143848

Inserm U 954, Faculté de Médecine de Nancy

no assertion criteria provided

probable-pathogenic

unknown

not provided

SCV001146717

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Pathogenic
(Sep 29, 2019)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness.

Jeannesson-Thivisol E, Feillet F, Chéry C, Perrin P, Battaglia-Hsu SF, Herbeth B, Cano A, Barth M, Fouilhoux A, Mention K, Labarthe F, Arnoux JB, Maillot F, Lenaerts C, Dumesnil C, Wagner K, Terral D, Broué P, de Parscau L, Gay C, Kuster A, Bédu A, et al.

Orphanet J Rare Dis. 2015 Dec 15;10:158. doi: 10.1186/s13023-015-0375-x.

PubMed [citation]

PMID:: 26666653
PMCID:: PMC5024853

Details of each submission

From Inserm U 954, Faculté de Médecine de Nancy, SCV000143848.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen PAH Variant Curation Expert Panel, SCV001146717.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The c.169G>T (p.Glu57Ter) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 120268); the collection method is stated as 'literature only' and no further information is provided. With respect to the published literature, it has been previously reported in one proband with classic PKU (defined by the authors as plasma phenylalanine levels > 1200umol/L) (PMID: 26666653) (PP4). The proband was said to be heterozygous for the variant and also harbor the known pathogenic allele (per ClinGen PAH working group classification, see ClinVar ID 636) c.194T>C (p.Ile65Thr); however, the manuscript did not specify whether the phase of the variants was confirmed via parental testing. Thus, at this point, PM3 cannot be applied with full confidence. The sequence change results in a nonsense variant which occurs in exon 3 of 13 in the in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (see PMID: 30192042) (PVS1). It is present at extremely low frequencies in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00014 in Other subpopulation in gnomAD, below the 0.0002 allele frequency cutoff for PAH variants (PM2).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

ClinVar

Relating variation to medicine