NM_001042492.3(NF1):c.1466A>G (p.Tyr489Cys) AND not provided

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jun 29, 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:: RCV000757556.20

Allele description [Variation Report for NM_001042492.3(NF1):c.1466A>G (p.Tyr489Cys)]

NM_001042492.3(NF1):c.1466A>G (p.Tyr489Cys)

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.1466A>G (p.Tyr489Cys)

HGVS:

NC_000017.11:g.31214524A>G
NG_009018.1:g.124548A>G
NM_000267.3:c.1466A>G
NM_001042492.3:c.1466A>GMANE SELECT
NM_001128147.3:c.1466A>G
NP_000258.1:p.Tyr489Cys
NP_001035957.1:p.Tyr489Cys
NP_001035957.1:p.Tyr489Cys
NP_001121619.1:p.Tyr489Cys
LRG_214t1:c.1466A>G
LRG_214t2:c.1466A>G
LRG_214:g.124548A>G
LRG_214p1:p.Tyr489Cys
LRG_214p2:p.Tyr489Cys
NC_000017.10:g.29541542A>G
NM_001042492.2:c.1466A>G
P21359:p.Tyr489Cys

Protein change:

Y489C; TYR489CYS

Links:

UniProtKB: P21359#VAR_032465; OMIM: 613113.0023; dbSNP: rs137854557

NCBI 1000 Genomes Browser:

rs137854557

Molecular consequence:

NM_000267.3:c.1466A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001042492.3:c.1466A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001128147.3:c.1466A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000885830	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jul 6, 2017)	germline	clinical testing	Citation Link,
SCV001470145	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jun 29, 2023)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 23758643, 27322474, 23668869, 27074763, 26969325, 24789688, 28422438, 26740943, 10862084, 10543400, 10607834, 11258625, 17426081, 10712197, 22190595, 26467025
SCV001476702	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Jun 29, 2023)	unknown	clinical testing	PubMed (16) [See all records that cite these PMIDs] 23758643, 27322474, 23668869, 27074763, 26969325, 24789688, 28422438, 26740943, 10862084, 10543400, 10607834, 11258625, 17426081, 10712197, 22190595, 26467025
SCV001772211	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 7, 2023)	germline	clinical testing	Citation Link,
SCV001955347	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
SCV001968585	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

Help

Summary from all submissions

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

Thirty-nine novel neurofibromatosis 1 (NF1) gene mutations identified in Slovak patients.

Nemethova M, Bolcekova A, Ilencikova D, Durovcikova D, Hlinkova K, Hlavata A, Kovacs L, Kadasi L, Zatkova A.

Ann Hum Genet. 2013 Sep;77(5):364-79. doi: 10.1111/ahg.12026. Epub 2013 Jun 12.

PubMed [citation]

PMID:: 23758643

Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only.

Evans DG, Bowers N, Burkitt-Wright E, Miles E, Garg S, Scott-Kitching V, Penman-Splitt M, Dobbie A, Howard E, Ealing J, Vassalo G, Wallace AJ, Newman W; Northern UK NF1 Research Network., Huson SM.

EBioMedicine. 2016 May;7:212-20. doi: 10.1016/j.ebiom.2016.04.005. Epub 2016 Apr 13.

PubMed [citation]

PMID:: 27322474
PMCID:: PMC4909377

See all PubMed Citations (16)

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885830.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470145.3

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

Description

Peer-reviewed experimental studies have demonstrated that this variant causes aberrant splicing resulting in a nonsense variant (p.Tyr489*) in the NF1 mRNA which causes premature termination of NF1 protein synthesis (PMID: 10543400 (1999), 11258625 (1999), and 10607834 (2000)). It has been reported in numerous Neurofibromatosis type 1 patients in the published literature (PMID: 23758643 (2013), 23668869 (2013), and 26740943 (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 Athena Diagnostics, SCV001476702.2

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

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals and families with NF1. In some published literature, this variant is referred to as 1466del62. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10543400, 11258625, and 10607834)

#	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 GeneDx, SCV001772211.4

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

Description

Exonic splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Osborn and Upadhyaya, 1999; Messiaen et al., 2000; Nemethova et al., 2013); In silico analysis supports a deleterious effect on splicing; 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: 29685074, 26056819, 12807981, 10862084, 10543400, 31533797, 34694046, 29922827, 34427956, 11258625, 10607834, 24803665, 25919870, 11258624, 12095621, 27074763, 19076627, 11735023, 23758643, 22155606, 15863657, 22190595, 15994866, 29666462, 29522274, 12566521, 30014477, 30290804, 30308447, 23668869, 30530636, 31766501, 31717729, 31370276, 29625052, 33372952, 31589614, 31776437, 34308104, 34945792, 33999308, 34992632)

#	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, SCV001955347.1

#	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, SCV001968585.1

#	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: May 7, 2024

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