NM_000277.3(PAH):c.838G>A (p.Glu280Lys) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Aug 31, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000078532.27

Allele description [Variation Report for NM_000277.3(PAH):c.838G>A (p.Glu280Lys)]

NM_000277.3(PAH):c.838G>A (p.Glu280Lys)

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.838G>A (p.Glu280Lys)

Other names:

p.E280K:GAA>AAA; p.E280K

HGVS:

NC_000012.12:g.102852819C>T
NG_008690.2:g.110592G>A
NM_000277.3:c.838G>AMANE SELECT
NM_001354304.2:c.838G>A
NP_000268.1:p.Glu280Lys
NP_000268.1:p.Glu280Lys
NP_001341233.1:p.Glu280Lys
NC_000012.11:g.103246597C>T
NM_000277.1:c.838G>A
P00439:p.Glu280Lys

Protein change:

E280K; GLU280LYS

Links:

UniProtKB: P00439#VAR_000980; OMIM: 612349.0004; dbSNP: rs62508698

NCBI 1000 Genomes Browser:

rs62508698

Molecular consequence:

NM_000277.3:c.838G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.838G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000110388	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Mar 2, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23500595, 2564729 Citation Link,
SCV000119733	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	no classification provided	not provided	not provided	not provided
SCV000239076	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 28, 2020)	germline	clinical testing	Citation Link,
SCV000888355	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Aug 31, 2020)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 2564729, 23500595, 2014036, 12655546, 17935162, 22763404, 30963030, 29499199, 26467025
SCV001952548	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	21	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency.

Lyonnet S, Caillaud C, Rey F, Berthelon M, Frézal J, Rey J, Munnich A.

Am J Hum Genet. 1989 Apr;44(4):511-7.

PubMed [citation]

PMID:: 2564729
PMCID:: PMC1715570

Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain.

Couce ML, Bóveda MD, Fernández-Marmiesse A, Mirás A, Pérez B, Desviat LR, Fraga JM.

Gene. 2013 May 25;521(1):100-4. doi: 10.1016/j.gene.2013.03.004. Epub 2013 Mar 14.

PubMed [citation]

PMID:: 23500595

See all PubMed Citations (9)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000110388.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	21	not provided	not provided	clinical testing	PubMed (2)

#	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		21	not provided	not provided	not provided

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119733.1

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

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

From GeneDx, SCV000239076.15

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

Description

Published functional studies demonstrate that E280K is associated no detectable residual enzyme activity (Pey et al., 2003; Pey et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 2014036, 21953985, 30747360, 9399896, 1971144, 25087612, 22975760, 23500595, 17935162, 25750018, 2564729, 28676969, 29499199, 29317692, 12655546, 9101291, 30037505, 30963030, 31355225, 31589614, 33101986, 17924342, 32778825, 29288420, 33375644)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000888355.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant was found in at least one symptomatic individual and predicted to have a damaging effect on the protein. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. It has also been reported to be associated with classic PKU and undetectable PAH enzyme activity (PMID: 12655546 (2003), 22763404(2012), 23500595 (2013), and 30963030 (2019)).

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001952548.1

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

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

Last Updated: Nov 3, 2024

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