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NM_000277.3(PAH):c.684A>C (p.Glu228Asp) AND Phenylketonuria

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 21, 2020
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:
RCV001375898.2

Allele description [Variation Report for NM_000277.3(PAH):c.684A>C (p.Glu228Asp)]

NM_000277.3(PAH):c.684A>C (p.Glu228Asp)

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.684A>C (p.Glu228Asp)
HGVS:
  • NC_000012.12:g.102855158T>G
  • NG_008690.2:g.108253A>C
  • NM_000277.3:c.684A>CMANE SELECT
  • NM_001354304.2:c.684A>C
  • NP_000268.1:p.Glu228Asp
  • NP_001341233.1:p.Glu228Asp
  • NC_000012.11:g.103248936T>G
Protein change:
E228D
Links:
dbSNP: rs2136649225
NCBI 1000 Genomes Browser:
rs2136649225
Molecular consequence:
  • NM_000277.3:c.684A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.684A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001572862ClinGen PAH Variant Curation Expert Panel
reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)		Uncertain significance
(Dec 21, 2020) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen PAH Variant Curation Expert Panel, SCV001572862.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

This c.684A>C (p.Glu228Asp) variant in PAH was reported in trans with pathogenic variant p.Arg243Gln in 1 patient with PAH deficiency (960μmol/L Phe) (PMID: 28982351). This variant was found at an amino acid residue where p.Glu228Lys, a likely pathogenic missense variant, has been seen before. Computational evidence for this missense variant is conflicting; predicted to be tolerated (SIFT), disease-causing (MutationTaster) and benign (PolyPhen2). This variant is absent from population databases gnomAD, 1000 Genomes, and ESP. In summary, this variant meets criteria to be classified as a variant of uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4.

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

Last Updated: Jun 23, 2024