NM_000277.2(PAH):c.1169A>G (p.Glu390Gly) AND Hyperphenylalaninemia, non-pku

Clinical significance:Pathogenic (Last evaluated: Jan 3, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000000656.4

Allele description [Variation Report for NM_000277.2(PAH):c.1169A>G (p.Glu390Gly)]

NM_000277.2(PAH):c.1169A>G (p.Glu390Gly)

Gene:
PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12q23.2
Genomic location:
Preferred name:
NM_000277.2(PAH):c.1169A>G (p.Glu390Gly)
Other names:
p.E390G:GAG>GGG
HGVS:
  • NC_000012.12:g.102843676T>C
  • NG_008690.2:g.119735A>G
  • NM_000277.2:c.1169A>G
  • NP_000268.1:p.Glu390Gly
  • NC_000012.11:g.103237454T>C
  • NG_008690.1:g.78927A>G
  • NM_000277.1:c.1169A>G
  • P00439:p.Glu390Gly
Protein change:
E390G; GLU390GLY
Links:
UniProtKB: P00439#VAR_001027; OMIM: 612349.0051; dbSNP: rs5030856
NCBI 1000 Genomes Browser:
rs5030856
Allele Frequency:
0.0001, GO-ESP
Molecular consequence:
  • NM_000277.2:c.1169A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hyperphenylalaninemia, non-pku
Synonyms:
Hyperphenylalaninemia
Identifiers:
MedGen: C0751435; Human Phenotype Ontology: HP:0004923

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000020806OMIMno assertion criteria providedPathogenic
(Aug 1, 1999)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000696428Integrated Genetics/Laboratory Corporation of Americacriteria provided, single submitter
Pathogenic
(Jan 3, 2017)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria.

Abadie V, Jaruzelska J, Lyonnet S, Millasseau P, Berthelon M, Rey F, Munnich A, Rey J.

Hum Mol Genet. 1993 Jan;2(1):31-4.

PubMed [citation]
PMID:
8098245

Large heterozygous deletion masquerading as homozygous missense mutation: a pitfall in diagnostic mutation analysis.

Zschocke J, Quak E, Knauer A, Fritz B, Aslan M, Hoffmann GF.

J Inherit Metab Dis. 1999 Aug;22(6):687-92.

PubMed [citation]
PMID:
10472529
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000020806.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

For discussion of the glu390-to-gly (E390G) mutation in the PAH gene that was found in compound heterozygous state in a patient with non-phenylketonuria hyperphenylalaninemia (see PKU, 261600) by Abadie et al. (1993), see 612349.0050.

Zschocke et al. (1999) described a child in whom PKU was apparently caused by homozygosity for the E390G mutation in exon 11 of the PAH gene. However, the clinical severity of the disease was not as mild as expected, the mutation was not identified in the father despite confirmed paternity, and the paternal allele showed a highly unusual pattern of polymorphic markers in the PAH gene. The patient was found to have a large deletion involving exons 9, 10, and 11 (612349.0064) of the PAH gene, and was thus a compound heterozygote, accounting for the more severe phenotype.

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

From Integrated Genetics/Laboratory Corporation of America, SCV000696428.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: The PAH c.1169A>G (p.Glu390Gly) variant involves the alteration of a conserved nucleotide, present in catalytic domain of the protein (Couce_2013) and is predicted to be damaging by 5/5 in silico tools. This variant was found in 12/121202 control chromosomes at a frequency of 0.000099, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant is widely described as one of the frequent pathogenic variants that causes hyperphenylalaninemia with consistent genotype-phenotype data and functional studies. Eight homozygotes with this variant were responsive to BH4 (Dobrowolski_2011) which can be attributed to mild functional effect of this variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.

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

Last Updated: Jul 21, 2018