U.S. flag

An official website of the United States government

NM_000277.3(PAH):c.1243G>A (p.Asp415Asn) AND PAH-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 11, 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:
RCV003415609.5

Allele description [Variation Report for NM_000277.3(PAH):c.1243G>A (p.Asp415Asn)]

NM_000277.3(PAH):c.1243G>A (p.Asp415Asn)

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.1243G>A (p.Asp415Asn)
Other names:
p.D415N:GAC>AAC; NM_000277.1(PAH):c.1243G>A
HGVS:
  • NC_000012.12:g.102840472C>T
  • NG_008690.2:g.122939G>A
  • NM_000277.3:c.1243G>AMANE SELECT
  • NM_001354304.2:c.1243G>A
  • NP_000268.1:p.Asp415Asn
  • NP_001341233.1:p.Asp415Asn
  • NC_000012.11:g.103234250C>T
  • NM_000277.1:c.1243G>A
  • P00439:p.Asp415Asn
Protein change:
D415N; ASP415ASN
Links:
UniProtKB: P00439#VAR_001039; OMIM: 612349.0043; dbSNP: rs62644499
NCBI 1000 Genomes Browser:
rs62644499
Molecular consequence:
  • NM_000277.3:c.1243G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.1243G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004115586PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Mar 11, 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, SCV004115586.1

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

Description

The PAH c.1243G>A variant is predicted to result in the amino acid substitution p.Asp415Asn. This variant has been reported in the heterozygous state with a second PAH pathogenic variant in numerous patients with mild hyperphenylalaninemia (MHP) (e.g., Economou-Petersen et al. 1992. PubMed ID: 1358789; Guldberg et al. 1996. PubMed ID: 8929956; Zhu et al. 2013. PubMed ID: 23932990; Trunzo et al. 2014. PubMed ID: 24296287; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653). We have also observed this variant internally, in the homozygous or presumed compound heterozygous state with a second pathogenic variant, in five patients with a biochemical or clinical diagnosis of hyperphenylalaninemia. In functional studies, the p.Asp415Asn substitution has been reported to reduce enzyme activity, with the BioPKU database reporting an average residual enzyme activity of 72% (Zurflüh et al. 2008. PubMed ID: 17935162; Himmelreich et al. 2018. PubMed ID: 30037505; http://www.biopku.org/pah/result-details-pah.asp?ID=582). The c.1243G>A (p.Asp415Asn) has been classified as ‘Pathogenic’ by the ClinGen PAH Variant Curation Expert Panel, as well as by several other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/617/). Based on these observations, we classify this variant as pathogenic.

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

Last Updated: Oct 20, 2024