NM_001042492.3(NF1):c.5610-2A>T AND Neurofibromatosis, type 1

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 16, 2022
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:: RCV000497085.8

Allele description [Variation Report for NM_001042492.3(NF1):c.5610-2A>T]

NM_001042492.3(NF1):c.5610-2A>T

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.5610-2A>T

HGVS:

NC_000017.11:g.31330294A>T
NG_009018.1:g.240318A>T
NM_000267.3:c.5547-2A>T
NM_001042492.3:c.5610-2A>TMANE SELECT
LRG_214t1:c.5547-2A>T
LRG_214t2:c.5610-2A>T
LRG_214:g.240318A>T
NC_000017.10:g.29657312A>T
NC_000017.10:g.29657312A>T
NM_001042492.2:c.5610-2A>T
NM_001042492.3:c.5610-2A>T

Links:

dbSNP: rs1135402876

NCBI 1000 Genomes Browser:

rs1135402876

Molecular consequence:

NM_000267.3:c.5547-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001042492.3:c.5610-2A>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Neurofibromatosis, type 1 (NF1)
Synonyms:: NEUROFIBROMATOSIS, TYPE I; VON RECKLINGHAUSEN DISEASE; Recklinghausen's disease; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018975; MedGen: C0027831; Orphanet: 636; OMIM: 162200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000588804	Medical Genetics, University of Parma	no assertion criteria provided	Likely pathogenic (Feb 2, 2017)	germline	clinical testing
SCV000782056	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001479120	Genome Diagnostics Laboratory, The Hospital for Sick Children	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 26, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002560132	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003443066	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 16, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26969325, 16199547, 10712197, 23913538, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

No correlation between NF1 mutation position and risk of optic pathway glioma in 77 unrelated NF1 patients.

Hutter S, Piro RM, Waszak SM, Kehrer-Sawatzki H, Friedrich RE, Lassaletta A, Witt O, Korbel JO, Lichter P, Schuhmann MU, Pfister SM, Tabori U, Mautner VF, Jones DTW.

Hum Genet. 2016 May;135(5):469-475. doi: 10.1007/s00439-016-1646-x. Epub 2016 Mar 11.

PubMed [citation]

PMID:: 26969325

See all PubMed Citations (6)

Details of each submission

From Medical Genetics, University of Parma, SCV000588804.1

#	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 Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782056.1

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

#	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 Genome Diagnostics Laboratory, The Hospital for Sick Children, SCV001479120.1

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

#	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 Genome-Nilou Lab, SCV002560132.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443066.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 431660). Disruption of this splice site has been observed in individual(s) with neurofibromatosis type 1 (PMID: 26969325). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 37 of the NF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538).

#	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: Jan 13, 2025

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