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NM_000277.3(PAH):c.1222C>T (p.Arg408Trp) AND PAH-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 1, 2023
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:
RCV003415607.5

Allele description [Variation Report for NM_000277.3(PAH):c.1222C>T (p.Arg408Trp)]

NM_000277.3(PAH):c.1222C>T (p.Arg408Trp)

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.1222C>T (p.Arg408Trp)
Other names:
p.R408W:CGG>TGG; NM_000277.1(PAH):c.1222C>T
HGVS:
  • NC_000012.12:g.102840493G>A
  • NG_008690.2:g.122918C>T
  • NM_000277.3:c.1222C>TMANE SELECT
  • NM_001354304.2:c.1222C>T
  • NP_000268.1:p.Arg408Trp
  • NP_000268.1:p.Arg408Trp
  • NP_001341233.1:p.Arg408Trp
  • NC_000012.11:g.103234271G>A
  • NM_000277.1:c.1222C>T
  • NM_000277.2:c.1222C>T
  • P00439:p.Arg408Trp
  • c.1222C>T (p.Arg408Trp)
Protein change:
R408W; ARG408TRP
Links:
UniProtKB: P00439#VAR_001035; OMIM: 612349.0002; dbSNP: rs5030858
NCBI 1000 Genomes Browser:
rs5030858
Molecular consequence:
  • NM_000277.3:c.1222C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.1222C>T - 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
SCV004115100PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jun 1, 2023) 		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, SCV004115100.1

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

Description

The PAH c.1222C>T variant is predicted to result in the amino acid substitution p.Arg408Trp. This variant is one of the most commonly reported pathogenic PAH variants and has been associated with classical phenylketonuria (PKU) (DiLella et al. 1987. PubMed ID: 2884570; Guldberg et al. 1994. PubMed ID: 8088845; Danecka et al. 2015. PubMed ID: 25596310). The p.Arg408Trp amino acid change has been reported to reduce the activity of the PAH protein to <2% of wild-type, and is reported to result in a PAH protein that is non-responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). Over 1800 patients homozygous for this variant have been reported in the BioPKU database; over 99% of the reported patients presented with classic PKU (http://www.biopku.org). The c.1222C>T variant is interpreted as pathogenic by the ClinGen PAH Variant Curation Expert Panel and other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/577/). We also interpret this variant as pathogenic.

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

Last Updated: Aug 25, 2024