NM_000277.3(PAH):c.835C>A (p.Pro279Thr) AND Phenylketonuria

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 29, 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:: RCV003597939.1

Allele description [Variation Report for NM_000277.3(PAH):c.835C>A (p.Pro279Thr)]

NM_000277.3(PAH):c.835C>A (p.Pro279Thr)

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.835C>A (p.Pro279Thr)

HGVS:

NC_000012.12:g.102852822G>T
NG_008690.2:g.110589C>A
NM_000277.3:c.835C>AMANE SELECT
NM_001354304.2:c.835C>A
NP_000268.1:p.Pro279Thr
NP_001341233.1:p.Pro279Thr
NC_000012.11:g.103246600G>T

Protein change:

P279T

Molecular consequence:

NM_000277.3:c.835C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.835C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004516805	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 29, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21890392, 32668217, 28492532 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004516805

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 29, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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

Citations

PubMed

The spectrum of phenylketonuria genotypes in the Armenian population: identification of three novel mutant PAH alleles.

Kostandyan N, Britschgi C, Matevosyan A, Oganezova A, Davtyan A, Blau N, Steinmann B, Thöny B.

Mol Genet Metab. 2011;104 Suppl:S93-6. doi: 10.1016/j.ymgme.2011.08.006. Epub 2011 Aug 12.

PubMed [citation]

PMID:: 21890392

The Genetic Landscape and Epidemiology of Phenylketonuria.

Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C, Chiesa AE, Christodoulou J, Đorđević M, Desviat LR, Eliyahu A, Evers RAF, Fajkusova L, Feillet F, Bonfim-Freitas PE, Giżewska M, Gundorova P, Karall D, Kneller K, Kutsev SI, Leuzzi V, Levy HL, et al.

Am J Hum Genet. 2020 Aug 6;107(2):234-250. doi: 10.1016/j.ajhg.2020.06.006. Epub 2020 Jul 14.

PubMed [citation]

PMID:: 32668217
PMCID:: PMC7413859

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004516805.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro279 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21890392, 32668217). 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 PAH-related conditions (PMID: 32668217; BIOPKU http://www.biopku.org). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 279 of the PAH protein (p.Pro279Thr).

#	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

Last Updated: Feb 28, 2024

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