U.S. flag

An official website of the United States government

NM_000277.3(PAH):c.838G>A (p.Glu280Lys) AND PAH-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 6, 2024
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
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:
RCV004739272.1

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]

Condition(s)

Name:
PAH-related disorder
Synonyms:
PAH-related condition
Identifiers:

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV005362913PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Mar 6, 2024) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV005362913.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The PAH c.838G>A variant is predicted to result in the amino acid substitution p.Glu280Lys. This is a commonly reported pathogenic variant that, in the homozygous state, has been associated with classic phenylketonuria (PKU) (e.g., Couce et al. 2013. PubMed ID: 23500595; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). The p.Glu280 amino acid has been reported to be located in the active site, and in functional assays the p.Glu280Lys substitution has essentially abolished PAH enzyme activity and resulted in a PAH protein that is non-responsive to BH4 (e.g., Pey et al. 2003. PubMed ID: 12655546; Zurflüh et al. 2008. PubMed ID: 17935162). Different substitutions of the same amino acid (p.Glu280Ala, p.Glu280Gly) have also been reported to be causative for phenylalanine hydroxylase deficiency (e.g., Aulehla-Scholz and Heilbronner. 2003. PubMed ID: 12655553; Song et al. 2005. PubMed ID: 16256386). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Multiple independent submitters to ClinVar have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/580). In summary, this variant is interpreted as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024