NM_000277.3(PAH):c.1199G>A (p.Arg400Lys) AND Phenylketonuria

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 24, 2023
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:: RCV000672156.4

Allele description [Variation Report for NM_000277.3(PAH):c.1199G>A (p.Arg400Lys)]

NM_000277.3(PAH):c.1199G>A (p.Arg400Lys)

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.1199G>A (p.Arg400Lys)

HGVS:

NC_000012.12:g.102843646C>T
NG_008690.2:g.119765G>A
NM_000277.3:c.1199G>AMANE SELECT
NM_001354304.2:c.1199G>A
NP_000268.1:p.Arg400Lys
NP_001341233.1:p.Arg400Lys
NC_000012.11:g.103237424C>T
NM_000277.1:c.1199G>A

Protein change:

R400K

Links:

dbSNP: rs199475658

NCBI 1000 Genomes Browser:

rs199475658

Molecular consequence:

NM_000277.3:c.1199G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1199G>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

Salmo trutta chromosome 8, fSalTru1.1, whole genome shotgun sequence
Salmo trutta chromosome 8, fSalTru1.1, whole genome shotgun sequence
gi|1693374042|gnl|ASM:GCF_901001164 r_scaffold_2|ref|NC_042964.1||gpp|GPC_000004979.1||gnl|NCBI_GENOMES|84540

Nucleotide
J_093015-circRNA-33 AS-CR-005 Human CircRNA V2 microarray 01272016
J_093015-circRNA-33 AS-CR-005 Human CircRNA V2 microarray 01272016
J_093015-circRNA-33 AS-CR-005 Human CircRNA V2 microarray 01272016

BioProject
Intestinal Perforation - StatPearls
Intestinal Perforation - StatPearls
LOC108326026 [Vigna angularis]
LOC108326026 [Vigna angularis]
Gene ID:108326026

Gene

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
SCV000797230	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jan 22, 2018)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17924342, 26503515, 16256386, 27264808, 23932990, 25456745 Citation Link,
SCV004294257	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 24, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17576681, 9536098, 16256386, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000797230

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))

Likely pathogenic
(Jan 22, 2018)

unknown

clinical testing

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

Citation Link,

SCV004294257

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 24, 2023)

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases.

Pey AL, Stricher F, Serrano L, Martinez A.

Am J Hum Genet. 2007 Nov;81(5):1006-24. Epub 2007 Oct 2.

PubMed [citation]

PMID:: 17924342
PMCID:: PMC2265664

Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing.

Li N, Jia H, Liu Z, Tao J, Chen S, Li X, Deng Y, Jin X, Song J, Zhang L, Liang Y, Wang W, Zhu J.

Sci Rep. 2015 Oct 27;5:15769. doi: 10.1038/srep15769.

PubMed [citation]

PMID:: 26503515
PMCID:: PMC4621502

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000797230.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294257.1

#	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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 102561). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 16256386). This variant is present in population databases (rs199475658, gnomAD 0.06%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 400 of the PAH protein (p.Arg400Lys). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon.

#	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