NM_000277.3(PAH):c.242C>A (p.Thr81Asn) AND Phenylketonuria

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Dec 10, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000190376.7

Allele description [Variation Report for NM_000277.3(PAH):c.242C>A (p.Thr81Asn)]

NM_000277.3(PAH):c.242C>A (p.Thr81Asn)

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.242C>A (p.Thr81Asn)

Other names:

NM_000277.2(PAH):c.242C>A

HGVS:

NC_000012.12:g.102894845G>T
NG_008690.2:g.68566C>A
NM_000277.3:c.242C>AMANE SELECT
NM_001354304.2:c.242C>A
NP_000268.1:p.Thr81Asn
NP_001341233.1:p.Thr81Asn
NC_000012.11:g.103288623G>T
NC_000012.11:g.103288623G>T
NM_000277.1:c.242C>A

Protein change:

T81N

Links:

dbSNP: rs796064502

NCBI 1000 Genomes Browser:

rs796064502

Molecular consequence:

NM_000277.3:c.242C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.242C>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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000243910	Inserm U 954, Faculté de Médecine de Nancy	no assertion criteria provided	probable-pathogenic	unknown	not provided
SCV000886571	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Dec 10, 2018)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV003441163	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 13, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 8659548, 23430918, 23942198, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000243910

Inserm U 954, Faculté de Médecine de Nancy

no assertion criteria provided

probable-pathogenic

unknown

not provided

SCV000886571

ClinGen PAH Variant Curation Expert Panel

reviewed by expert panel

(ClinGen PAH ACMG Specifications v1)

Likely pathogenic
(Dec 10, 2018)

germline

curation

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

Citation Link,

SCV003441163

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 13, 2022)

germline

clinical testing

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

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, curation
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	not provided

Citations

PubMed

Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study.

Guldberg P, Levy HL, Hanley WB, Koch R, Matalon R, Rouse BM, Trefz F, de la Cruz F, Henriksen KF, Güttler F.

Am J Hum Genet. 1996 Jul;59(1):84-94.

PubMed [citation]

PMID:: 8659548
PMCID:: PMC1915123

Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response?

Sarkissian CN, Gamez A, Scott P, Dauvillier J, Dorenbaum A, Scriver CR, Stevens RC.

JIMD Rep. 2012;5:59-70. doi: 10.1007/8904_2011_96. Epub 2011 Dec 6.

PubMed [citation]

PMID:: 23430918
PMCID:: PMC3509924

See all PubMed Citations (4)

Details of each submission

From Inserm U 954, Faculté de Médecine de Nancy, SCV000243910.1

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

Description

Converted during submission to Likely pathogenic.

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

From ClinGen PAH Variant Curation Expert Panel, SCV000886571.2

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

Description

The c.242C>A (p.Thr81Asn) variant in PAH is reported in 1 PKU patient. PAH and BH4DH genes were sequenced. It was detected with p.V230I which is interpreted as Pathogenic/Likely Pathogenic in ClinVar. (PMID: 23942198) This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, MutationTaster, and Polyphen-2. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003441163.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr81 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8659548, 23430918). 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 not expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 208180). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 23942198; Invitae). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 81 of the PAH protein (p.Thr81Asn).

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine