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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002238710	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 17, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11708866, 16198137, 16601866, 28492532
SCV004209674	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002238710

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 17, 2021)

germline

clinical testing

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

SCV004209674

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 27, 2024)

unknown

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004209674.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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