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NM_000277.3(PAH):c.811C>A (p.His271Asn) AND Phenylketonuria

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 28, 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:
RCV003599095.1

Allele description

NM_000277.3(PAH):c.811C>A (p.His271Asn)

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.811C>A (p.His271Asn)
HGVS:
  • NC_000012.12:g.102852846G>T
  • NG_008690.2:g.110565C>A
  • NM_000277.3:c.811C>AMANE SELECT
  • NM_001354304.2:c.811C>A
  • NP_000268.1:p.His271Asn
  • NP_001341233.1:p.His271Asn
  • NC_000012.11:g.103246624G>T
Protein change:
H271N
Molecular consequence:
  • NM_000277.3:c.811C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.811C>A - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV004413919Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jul 28, 2023)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene.

Bercovich D, Elimelech A, Zlotogora J, Korem S, Yardeni T, Gal N, Goldstein N, Vilensky B, Segev R, Avraham S, Loewenthal R, Schwartz G, Anikster Y.

J Hum Genet. 2008;53(5):407-418. doi: 10.1007/s10038-008-0264-4. Epub 2008 Feb 26.

PubMed [citation]
PMID:
18299955

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV004413919.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 271 of the PAH protein (p.His271Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (Invitae). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. This variant disrupts the p.His271 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18299955). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Feb 28, 2024