NM_001042492.3(NF1):c.58C>T (p.Gln20Ter) AND Neurofibromatosis, type 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jul 6, 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:: RCV000698970.8

Allele description [Variation Report for NM_001042492.3(NF1):c.58C>T (p.Gln20Ter)]

NM_001042492.3(NF1):c.58C>T (p.Gln20Ter)

Genes:

MIR4733HG:MIR4733 host gene [Gene - HGNC]
LOC111811965:NF1 (neurofibromin 1) promoter region [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.58C>T (p.Gln20Ter)

HGVS:

NC_000017.11:g.31095367C>T
NG_009018.1:g.5391C>T
NG_056197.1:g.1863C>T
NM_000267.3:c.58C>T
NM_001042492.3:c.58C>TMANE SELECT
NM_001128147.3:c.58C>T
NP_000258.1:p.Gln20Ter
NP_001035957.1:p.Gln20Ter
NP_001121619.1:p.Gln20Ter
LRG_214t1:c.58C>T
LRG_214:g.5391C>T
LRG_214p1:p.Gln20Ter
NC_000017.10:g.29422385C>T
NM_001042492.3:c.58C>T

Protein change:

Q20*

Links:

dbSNP: rs1567786905

NCBI 1000 Genomes Browser:

rs1567786905

Molecular consequence:

NM_000267.3:c.58C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001042492.3:c.58C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001128147.3:c.58C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000827661	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18546366, 28492532
SCV001479160	Genome Diagnostics Laboratory, The Hospital for Sick Children	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 26, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002561540	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000827661

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 6, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001479160

Genome Diagnostics Laboratory, The Hospital for Sick Children

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 26, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002561540

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]

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	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations.

Pros E, Gómez C, Martín T, Fábregas P, Serra E, Lázaro C.

Hum Mutat. 2008 Sep;29(9):E173-93. doi: 10.1002/humu.20826.

PubMed [citation]

PMID:: 18546366

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000827661.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

ClinVar contains an entry for this variant (Variation ID: 576465). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 18546366). The resulting mRNA is expected to undergo nonsense-mediated decay. This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 18546366). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln20*) in the NF1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product.

#	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 Diagnostics Laboratory, The Hospital for Sick Children, SCV001479160.1

#	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, SCV002561540.1

#	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

Last Updated: Jun 9, 2024

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