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NM_000277.3(PAH):c.275C>T (p.Thr92Ile) AND Phenylketonuria

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Mar 27, 2024
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001854512.6

Allele description [Variation Report for NM_000277.3(PAH):c.275C>T (p.Thr92Ile)]

NM_000277.3(PAH):c.275C>T (p.Thr92Ile)

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.275C>T (p.Thr92Ile)
HGVS:
  • NC_000012.12:g.102894812G>A
  • NG_008690.2:g.68599C>T
  • NM_000277.3:c.275C>TMANE SELECT
  • NM_001354304.2:c.275C>T
  • NP_000268.1:p.Thr92Ile
  • NP_001341233.1:p.Thr92Ile
  • NC_000012.11:g.103288590G>A
  • NM_000277.1:c.275C>T
  • P00439:p.Thr92Ile
Protein change:
T92I
Links:
UniProtKB: P00439#VAR_000889; dbSNP: rs62514903
NCBI 1000 Genomes Browser:
rs62514903
Molecular consequence:
  • NM_000277.3:c.275C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354304.2:c.275C>T - 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
SCV002238710Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Nov 17, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004209674Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 27, 2024)
unknownclinical testing

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

Summary from all submissions

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

Citations

PubMed

PAH gene mutations in the Sicilian population: association with minihaplotypes and expression analysis.

Mirisola MG, Cali F, Gloria A, Schinocca P, D'Amato M, Cassara G, Leo GD, Palillo L, Meli C, Romano V.

Mol Genet Metab. 2001 Nov;74(3):353-61.

PubMed [citation]
PMID:
11708866

Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients.

Fiori L, Fiege B, Riva E, Giovannini M.

Mol Genet Metab. 2005 Dec;86 Suppl 1:S67-74. Epub 2005 Sep 28.

PubMed [citation]
PMID:
16198137
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002238710.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 11708866). 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 not expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102643). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 11708866, 16198137, 16601866). This variant is present in population databases (rs62514903, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 92 of the PAH protein (p.Thr92Ile).

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

From Baylor Genetics, SCV004209674.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024