NM_000277.3(PAH):c.473G>A (p.Arg158Gln) AND not provided

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Oct 21, 2021
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:: RCV000078522.46

Allele description [Variation Report for NM_000277.3(PAH):c.473G>A (p.Arg158Gln)]

NM_000277.3(PAH):c.473G>A (p.Arg158Gln)

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.473G>A (p.Arg158Gln)

Other names:

p.R158Q:CGG>CAG; NM_000277.2(PAH):c.473G>A

HGVS:

NC_000012.12:g.102866632C>T
NG_008690.2:g.96779G>A
NM_000277.3:c.473G>AMANE SELECT
NM_001354304.2:c.473G>A
NP_000268.1:p.Arg158Gln
NP_000268.1:p.Arg158Gln
NP_001341233.1:p.Arg158Gln
NC_000012.11:g.103260410C>T
NM_000277.1:c.473G>A
NM_000277.2:c.473G>A
P00439:p.Arg158Gln
c.473G>A (p.Arg158Gln)

Protein change:

R158Q; ARG158GLN

Links:

UniProtKB: P00439#VAR_000901; OMIM: 612349.0010; dbSNP: rs5030843

NCBI 1000 Genomes Browser:

rs5030843

Molecular consequence:

NM_000277.3:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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
SCV000110378	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Oct 26, 2016)	germline	clinical testing	Citation Link,
SCV000119542	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	no classification provided	not provided	not provided	not provided
SCV000239054	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 4, 2020)	germline	clinical testing	Citation Link,
SCV000601714	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 21, 2021)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 31589614, 31355225, 30747360, 2606484, 23500595, 22975760, 2014036, 12655546, 25750018, 26803807, 21953985, 19036622, 25087612, 27264808, 17935162, 26467025
SCV001501430	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Dec 1, 2020)	germline	clinical testing	Citation Link,
SCV001930656	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001958602	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001970641	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002525810	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 3, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11161839, 17935162, 19036622, 2014036, 23500595, 24190797, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	14	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

Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.

Capalbo A, Valero RA, Jimenez-Almazan J, Pardo PM, Fabiani M, Jiménez D, Simon C, Rodriguez JM.

PLoS Genet. 2019 Oct;15(10):e1008409. doi: 10.1371/journal.pgen.1008409.

PubMed [citation]

PMID:: 31589614
PMCID:: PMC6797235

The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra.

Su Y, Wang H, Rejiafu N, Wu B, Jiang H, Chen H, A X, Qian Y, Li M, Lu Y, Ren Y, Li L, Zhou W.

Ann Transl Med. 2019 Jun;7(12):258. doi: 10.21037/atm.2019.05.16.

PubMed [citation]

PMID:: 31355225
PMCID:: PMC6614323

See all PubMed Citations (19)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000110378.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	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		14	not provided	not provided	not provided

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119542.1

#	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, SCV000239054.10

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

Description

Associated with significantly reduced enzyme activity compared to wild type (Steventon et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; BH4 responsiveness has been inconsistent in patients with R158Q (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 26210745, 27264808, 25087612, 30963030, 31355225, 17924342, 22975760, 12655546, 2014036, 21953985, 19036622, 2606484, 17935162, 28754886, 29288420, 29111448, 28956315, 29316886, 28676969, 23500595, 25750018, 26803807, 29499199, 30747360, 31589614, 33101986, 8188310)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601714.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

In the published literature, the variant has been reported in individuals affected by Phenylketonuria (PKU) (PMIDs: 2606484 (1989), 12655546 (2003), 30747360 (2019), and 31355225 (2019)). Functional studies show that this variant is predicted to negatively impact protein function (PMIDs: 12655546 (2003), 17935162 (2008), 19036622 (2009), 21953985 (2012), and 25750018 (2015)). Based on the available information, this variant is classified as pathogenic.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001501430.23

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

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001930656.1

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001958602.1

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001970641.1

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV002525810.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

PP3, PM2, PM3_very_strong, PM5, PS3

#	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: Nov 10, 2024

Relating variation to medicine