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NM_000277.3(PAH):c.472C>G (p.Arg158Gly) AND Phenylketonuria

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 14, 2022
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:
RCV003598234.1

Allele description [Variation Report for NM_000277.3(PAH):c.472C>G (p.Arg158Gly)]

NM_000277.3(PAH):c.472C>G (p.Arg158Gly)

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.472C>G (p.Arg158Gly)
HGVS:
  • NC_000012.12:g.102866633G>C
  • NG_008690.2:g.96778C>G
  • NM_000277.3:c.472C>GMANE SELECT
  • NM_001354304.2:c.472C>G
  • NP_000268.1:p.Arg158Gly
  • NP_001341233.1:p.Arg158Gly
  • NC_000012.11:g.103260411G>C
Protein change:
R158G
Molecular consequence:
  • NM_000277.3:c.472C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.472C>G - 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
SCV004375313Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Dec 14, 2022)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Long-term beneficial effects of the phenylalanine-restricted diet in late-diagnosed individuals with phenylketonuria.

Koch R, Moseley K, Ning J, Romstad A, Guldberg P, Guttler F.

Mol Genet Metab. 1999 Jun;67(2):148-55.

PubMed [citation]
PMID:
10356314

Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene.

Shintaku H, Kure S, Ohura T, Okano Y, Ohwada M, Sugiyama N, Sakura N, Yoshida I, Yoshino M, Matsubara Y, Suzuki K, Aoki K, Kitagawa T.

Pediatr Res. 2004 Mar;55(3):425-30. Epub 2003 Dec 17.

PubMed [citation]
PMID:
14681498
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV004375313.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg158 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10356314, 14681498, 25894915, 26666653). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 missense change has been observed in individual(s) with phenylketonuria (PMID: 32668217; BIOPKU http://www.biopku.org). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 158 of the PAH protein (p.Arg158Gly).

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

Last Updated: Feb 28, 2024