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NM_000277.3(PAH):c.838G>A (p.Glu280Lys) AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 29, 2020
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002512608.9

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:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003651402Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jul 29, 2020) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Molecular basis of phenotypic heterogeneity in phenylketonuria.

Okano Y, Eisensmith RC, Güttler F, Lichter-Konecki U, Konecki DS, Trefz FK, Dasovich M, Wang T, Henriksen K, Lou H, et al.

N Engl J Med. 1991 May 2;324(18):1232-8.

PubMed [citation]
PMID:
2014036

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
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV003651402.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The alteration results in an amino acid change:_x000D_ _x000D_ The c.838G>A (p.E280K) alteration is located in coding exon 7 of the PAH gene. This alteration results from a G to A substitution at nucleotide position 838, causing the glutamic acid (E) at amino acid position 280 to be replaced by a lysine (K). The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the PAH c.838G>A alteration was observed in 0.006% (16/282,678) of total alleles studied, with a frequency of 0.008% (10/128,998) in the European (non-Finnish) subpopulation. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been reported homozygous or compound heterozygous with another mutation in PAH in multiple unrelated patients with phenylalanine hydroxylase (PAH) deficiency (Lyonnet, 1989; Okano, 1991; Su, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.E280 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Functional analysis demonstrated that the E280K alteration decreases PAH activity significantly compared to wild-type (Zurflüh, 2008; Shi, 2012). Three-dimensional structural analysis of the protein reveals that this alteration is an active site mutation (Pey, 2003). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.E280K alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

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

Last Updated: Nov 3, 2024