NM_001042492.3(NF1):c.5488C>T (p.Arg1830Cys) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jul 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:: RCV000439869.39

Allele description [Variation Report for NM_001042492.3(NF1):c.5488C>T (p.Arg1830Cys)]

NM_001042492.3(NF1):c.5488C>T (p.Arg1830Cys)

Gene:

NF1:neurofibromin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q11.2

Genomic location:

Preferred name:

NM_001042492.3(NF1):c.5488C>T (p.Arg1830Cys)

HGVS:

NC_000017.11:g.31327718C>T
NG_009018.1:g.237742C>T
NM_000267.3:c.5425C>T
NM_001042492.3:c.5488C>TMANE SELECT
NP_000258.1:p.Arg1809Cys
NP_001035957.1:p.Arg1830Cys
LRG_214t1:c.5425C>T
LRG_214:g.237742C>T
LRG_214p1:p.Arg1809Cys
NC_000017.10:g.29654736C>T
NM_001042492.2:c.5488C>T
NM_001042492.3:c.5488C>T

Protein change:

R1809C

Links:

dbSNP: rs797045139

NCBI 1000 Genomes Browser:

rs797045139

Molecular consequence:

NM_000267.3:c.5425C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042492.3:c.5488C>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
SCV000521065	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 2, 2020)	germline	clinical testing	Citation Link,
SCV001500115	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jul 1, 2024)	germline	clinical testing	Citation Link,
SCV002037223	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
SCV002037696	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
SCV004222176	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jan 15, 2019)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 28135719, 25370043, 24357598, 26178382, 25966637, 12807981, 18183640, 19120036, 26467025
SCV004224694	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 20, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	6	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
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Prevalence and architecture of de novo mutations in developmental disorders.

Deciphering Developmental Disorders Study.

Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.

PubMed [citation]

PMID:: 28135719
PMCID:: PMC6016744

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas.

Pinna V, Lanari V, Daniele P, Consoli F, Agolini E, Margiotti K, Bottillo I, Torrente I, Bruselles A, Fusilli C, Ficcadenti A, Bargiacchi S, Trevisson E, Forzan M, Giustini S, Leoni C, Zampino G, Digilio MC, Dallapiccola B, Clementi M, Tartaglia M, De Luca A.

Eur J Hum Genet. 2015 Aug;23(8):1068-71. doi: 10.1038/ejhg.2014.243. Epub 2014 Nov 5.

PubMed [citation]

PMID:: 25370043
PMCID:: PMC4795103

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000521065.6

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

Description

p.Arg1809 missense variants account for approximately 1% of individuals with neurofibromatosis type 1 (Rojnueangnit et al., 2015); Not observed in large population cohorts (gnomAD); 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: 27322474, 12807981, 26457592, 25533962, 27171602, 28135719, 19120036, 24789688, 28191890, 29522274, 18183640, 24357598, 26178382, 31730495, 31717729, 31370276, 32107864, 33482836, 32427313, 31785789, 25966637, 25370043)

#	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, SCV001500115.24

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

Description

NF1: PM2, PM5, PM6, PS4:Moderate, PP2, PP3

#	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		3	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV002037223.1

#	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, SCV002037696.1

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004222176.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant has been reported in multiple individuals and families with a distinctive presentation of mild NF1 overlapping with features of Noonan syndrome in the published literature (PMID: 26178382 (2015), 25966637 (2015), 25370043 (2015), 24357598 (2014), 19120036 (2009), 18183640 (2007), 12807981 (2003)). The variant has been reported to occur de novo (PMID: 28135719 (2017)). Analysis of this variant using bioinformatics tools (e.g. MutationTaster and PolyPhen-2) for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV004224694.1

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

Description

PP1_strong, PP2, PP3, PP4, PP5, PM2, PM6_very_strong, PS4_moderate

#	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

Last Updated: Jan 13, 2025

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