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NM_000277.3(PAH):c.1223G>A (p.Arg408Gln) AND PAH-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 16, 2024
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:
RCV003934788.2

Allele description [Variation Report for NM_000277.3(PAH):c.1223G>A (p.Arg408Gln)]

NM_000277.3(PAH):c.1223G>A (p.Arg408Gln)

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.1223G>A (p.Arg408Gln)
Other names:
NM_000277.1(PAH):c.1223G>A
HGVS:
  • NC_000012.12:g.102840492C>T
  • NG_008690.2:g.122919G>A
  • NM_000277.3:c.1223G>AMANE SELECT
  • NM_001354304.2:c.1223G>A
  • NP_000268.1:p.Arg408Gln
  • NP_001341233.1:p.Arg408Gln
  • NC_000012.11:g.103234270C>T
  • NM_000277.1:c.1223G>A
  • NM_000277.2:c.1223G>A
  • P00439:p.Arg408Gln
  • c.1223G>A (p.Arg408Gln)
Protein change:
R408Q; ARG408GLN
Links:
UniProtKB: P00439#VAR_001034; OMIM: 612349.0038; dbSNP: rs5030859
NCBI 1000 Genomes Browser:
rs5030859
Molecular consequence:
  • NM_000277.3:c.1223G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.1223G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004750289PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Feb 16, 2024) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004750289.1

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

Description

The PAH c.1223G>A variant is predicted to result in the amino acid substitution p.Arg408Gln. This variant has been reported in the homozygous state or with a second pathogenic PAH variant in many patients with phenylalanine hydroxylase deficiency (e.g., Zschocke et al. 1995. PubMed ID: 8533759; Eiken et al. 1996. PubMed ID: 8875186; Table S3, Hillert et al. 2020. PubMed ID: 32668217). The p.Arg408Gln amino acid substitution has been reported to reduce PAH enzyme activity to ~50% of wild-type (Zurflüh et al. 2008. PubMed ID: 17935162) and is generally considered a mild PAH variant (Liang et al. 2014. PubMed ID: 24401910). This variant has been classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as several other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/612/). Over twenty patients homozygous for the c.1223G>A (p.Arg408Gln) variant have been reported in the BioPKU database; the majority of these patients presented with mild hyperphenylalaninemia or mild PKU (http://www.biopku.org). In summary, we classify the c.1223G>A variant as pathogenic.

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

Last Updated: Jul 7, 2024