NM_000277.3(PAH):c.1169A>G (p.Glu390Gly) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 10, 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:: RCV000078503.43

Allele description [Variation Report for NM_000277.3(PAH):c.1169A>G (p.Glu390Gly)]

NM_000277.3(PAH):c.1169A>G (p.Glu390Gly)

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.1169A>G (p.Glu390Gly)

Other names:

p.E390G:GAG>GGG; NM_000277.1(PAH):c.1169A>G

HGVS:

NC_000012.12:g.102843676T>C
NG_008690.2:g.119735A>G
NM_000277.3:c.1169A>GMANE SELECT
NM_001354304.2:c.1169A>G
NP_000268.1:p.Glu390Gly
NP_000268.1:p.Glu390Gly
NP_001341233.1:p.Glu390Gly
NC_000012.11:g.103237454T>C
NM_000277.1:c.1169A>G
P00439:p.Glu390Gly

Protein change:

E390G; GLU390GLY

Links:

UniProtKB: P00439#VAR_001027; OMIM: 612349.0051; dbSNP: rs5030856

NCBI 1000 Genomes Browser:

rs5030856

Molecular consequence:

NM_000277.3:c.1169A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.1169A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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galntl6 polypeptide N-acetylgalactosaminyltransferase like 6 [Danio rerio]
galntl6 polypeptide N-acetylgalactosaminyltransferase like 6 [Danio rerio]
Gene ID:568915

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000110359	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Sep 27, 2013)	germline	clinical testing	Citation Link,
SCV000119363	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	no classification provided	not provided	not provided	not provided
SCV000239089	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 10, 2023)	germline	clinical testing	Citation Link,
SCV001247322	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2021)	germline	clinical testing	Citation Link,
SCV002047254	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 21, 2020)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10472529, 11161839, 24628256, 22698810, 19394257, 25596310, 21147011, 22300847, 26803807, 32668217, 31623983, 26467025

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	6	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Large heterozygous deletion masquerading as homozygous missense mutation: a pitfall in diagnostic mutation analysis.

Zschocke J, Quak E, Knauer A, Fritz B, Aslan M, Hoffmann GF.

J Inherit Metab Dis. 1999 Aug;22(6):687-92.

PubMed [citation]

PMID:: 10472529

In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: correlation with metabolic phenotypes and susceptibility toward protein aggregation.

Gjetting T, Petersen M, Guldberg P, Güttler F.

Mol Genet Metab. 2001 Feb;72(2):132-43.

PubMed [citation]

PMID:: 11161839

See all PubMed Citations (12)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000110359.8

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

#	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		6	not provided	not provided	not provided

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119363.1

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

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

From GeneDx, SCV000239089.14

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as being a tetrahydrobiopterin (BH4) responsive variant (PMID: 17935162, 23559577); This variant is associated with the following publications: (PMID: 10472529, 25750018, 23500595, 34828281, 31355225, 26666653, 30963030, 21147011, 22763404, 25087612, 8088845, 11914042, 25596310, 8098245, 28676969, 24048906, 22300847, 15557004, 26803807, 10479481, 31589614, 34426522, 33375644, 32778825, 33465300, 29288420, 23792259, 23559577, 35355500, 36537053, 35328070, 35339094, 35405047, 17935162)

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

From CeGaT Center for Human Genetics Tuebingen, SCV001247322.25

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047254.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The variant has been reported in multiple homozygous and compound heterozygous individuals affected with mild hyperphenylalaninemia or mild PKU and has been characterized as BH4-responsive in the published literature (PMID: 10472529 (1999), 19394257 (2009), 21147011 (2011), 22300847 (2012), 26803807 (2016), 31623983 (2019)). Functional studies have shown this variant reduces PAH activity to 42-62% (PMID: 21147011 (2011), 22300847 (2012), 26803807 (2016)).

#	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 13, 2024

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