NM_000277.3(PAH):c.721C>T (p.Arg241Cys) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Mar 1, 2024
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:: RCV000089054.42

Allele description [Variation Report for NM_000277.3(PAH):c.721C>T (p.Arg241Cys)]

NM_000277.3(PAH):c.721C>T (p.Arg241Cys)

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.721C>T (p.Arg241Cys)

Other names:

p.R241C:CGC>TGC; NM_000277.1(PAH):c.721C>T

HGVS:

NC_000012.12:g.102852936G>A
NG_008690.2:g.110475C>T
NM_000277.3:c.721C>TMANE SELECT
NM_001354304.2:c.721C>T
NP_000268.1:p.Arg241Cys
NP_000268.1:p.Arg241Cys
NP_001341233.1:p.Arg241Cys
NC_000012.11:g.103246714G>A
NM_000277.1:c.721C>T
P00439:p.Arg241Cys

Protein change:

R241C

Links:

UniProtKB: P00439#VAR_000943; dbSNP: rs76687508

NCBI 1000 Genomes Browser:

rs76687508

Molecular consequence:

NM_000277.3:c.721C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.721C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000119659	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	no classification provided	not provided	not provided	not provided
SCV000203183	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Jul 28, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10484807, 14722928, 17935162, 8222245 Citation Link,
SCV000239066	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 10, 2022)	germline	clinical testing	Citation Link,
SCV001370958	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2024)	germline	clinical testing	Citation Link,
SCV001927095	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
SCV001959600	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

Help

Summary from all submissions

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

Citations

PubMed

Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.

Kure S, Hou DC, Ohura T, Iwamoto H, Suzuki S, Sugiyama N, Sakamoto O, Fujii K, Matsubara Y, Narisawa K.

J Pediatr. 1999 Sep;135(3):375-8.

PubMed [citation]

PMID:: 10484807

Mutation spectrum in Taiwanese patients with phenylalanine hydroxylase deficiency and a founder effect for the R241C mutation.

Chien YH, Chiang SC, Huang A, Chou SP, Tseng SS, Huang YT, Hwu WL.

Hum Mutat. 2004 Feb;23(2):206. doi: 10.1002/humu.9215.

PubMed [citation]

PMID:: 14722928

See all PubMed Citations (4)

Details of each submission

From DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE, SCV000119659.1

#	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 Eurofins Ntd Llc (ga), SCV000203183.7

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

#	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		4	not provided	not provided	not provided

From GeneDx, SCV000239066.12

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

Description

Associated with mild hyperphenylalaninemia or mild phenylketonuria (PKU), although it has also been reported in an individual with classic PKU (Chien et al., 2004; Lee et al., 2008; Liang et al., 2014); R241C is associated with reduced residual PAH enzyme activity (Liang et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11486900, 25750018, 9860305, 18985011, 9634518, 8222245, 14722928, 27264808, 29499199, 29317692, 11243094, 29961769, 30678510, 30747360, 30275481, 34426522, 33677757, 32668217, 32778825, 30037505, 17935162, 24401910, 31053953)

#	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, SCV001370958.25

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

Description

PAH: PM3:Very Strong, PM2, PM5, PP3, PP4, PS3:Supporting

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001927095.1

#	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, SCV001959600.1

#	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

Last Updated: Mar 11, 2025

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