NM_001042492.3(NF1):c.1062+3A>G AND Neurofibromatosis, type 1

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Dec 22, 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:: RCV000583516.10

Allele description [Variation Report for NM_001042492.3(NF1):c.1062+3A>G]

NM_001042492.3(NF1):c.1062+3A>G

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.1062+3A>G

HGVS:

NC_000017.11:g.31200598A>G
NG_009018.1:g.110622A>G
NM_000267.3:c.1062+3A>G
NM_001042492.3:c.1062+3A>GMANE SELECT
NM_001128147.3:c.1062+3A>G
LRG_214t1:c.1062+3A>G
LRG_214:g.110622A>G
NC_000017.10:g.29527616A>G
NM_001042492.3:c.1062+3A>G

Links:

dbSNP: rs1057521098

NCBI 1000 Genomes Browser:

rs1057521098

Molecular consequence:

NM_000267.3:c.1062+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001042492.3:c.1062+3A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001128147.3:c.1062+3A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Neurofibromatosis, type 1 (NF1)
Synonyms:: NEUROFIBROMATOSIS, TYPE I; Recklinghausen's disease; Von Recklinghausen 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
SCV000692340	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	no assertion criteria provided	Uncertain significance (Jun 3, 2016)	germline	clinical testing
SCV000948669	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17576681, 9536098, 18546366, 32123317, 28492532
SCV002561625	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 15, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002567794	Medical Genetics, University of Parma	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 17, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002819462	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 12, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18546366, 32123317, 33804961 Citation Link

Help

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

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (7)

Details of each submission

From Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital, SCV000692340.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000948669.5

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

Description

This sequence change falls in intron 9 of the NF1 gene. It does not directly change the encoded amino acid sequence of the NF1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 18546366; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 381606). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9, but is expected to preserve the integrity of the reading-frame (PMID: 18546366, 32123317). For these reasons, this variant has been classified as Pathogenic.

#	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 Genome-Nilou Lab, SCV002561625.1

#	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 Medical Genetics, University of Parma, SCV002567794.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819462.1

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

Description

Variant summary: NF1 c.1062+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5 prime splicing donor site; two predict the variant weakens a 5 prime donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Pros_2018, Wai_2020). The variant allele was found at a frequency of 3.8e-06 in 265890 control chromosomes. c.1062+3A>G has been reported in the literature in at least one individual with diagnosis or clinical suspicion of neurofibromatosis type 1. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=2, likely pathogenic n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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: Sep 29, 2024

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