NM_001042492.3(NF1):c.1005T>C (p.Asn335=) AND not specified

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Apr 9, 2020
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:: RCV000613914.6

Allele description [Variation Report for NM_001042492.3(NF1):c.1005T>C (p.Asn335=)]

NM_001042492.3(NF1):c.1005T>C (p.Asn335=)

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.1005T>C (p.Asn335=)

HGVS:

NC_000017.11:g.31200538T>C
NG_009018.1:g.110562T>C
NM_000267.3:c.1005T>C
NM_001042492.3:c.1005T>CMANE SELECT
NM_001128147.3:c.1005T>C
NP_000258.1:p.Asn335=
NP_001035957.1:p.Asn335=
NP_001035957.1:p.Asn335=
NP_001121619.1:p.Asn335=
LRG_214t1:c.1005T>C
LRG_214t2:c.1005T>C
LRG_214:g.110562T>C
LRG_214p1:p.Asn335=
LRG_214p2:p.Asn335=
NC_000017.10:g.29527556T>C
NM_001042492.2:c.1005T>C
NM_001042492.3:c.1005T>C
p.N335N

Links:

dbSNP: rs777369021

NCBI 1000 Genomes Browser:

rs777369021

Molecular consequence:

NM_000267.3:c.1005T>C - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001042492.3:c.1005T>C - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001128147.3:c.1005T>C - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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LOC105371951 [Homo sapiens]
LOC105371951 [Homo sapiens]
Gene ID:105371951

Gene
LOC107985151 [Homo sapiens]
LOC107985151 [Homo sapiens]
Gene ID:107985151

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000718635	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Jan 2, 2018)	germline	clinical testing	Citation Link,
SCV001362235	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Mar 14, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10678181, 23460398, 29872168 Citation Link,
SCV002068089	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 9, 2020)	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

SCV000718635

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Jan 2, 2018)

germline

clinical testing

Citation Link,

SCV001362235

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Mar 14, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002068089

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Apr 9, 2020)

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	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

Nf1 and Gmcsf interact in myeloid leukemogenesis.

Birnbaum RA, O'Marcaigh A, Wardak Z, Zhang YY, Dranoff G, Jacks T, Clapp DW, Shannon KM.

Mol Cell. 2000 Jan;5(1):189-95.

PubMed [citation]

PMID:: 10678181

Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia.

Boudry-Labis E, Roche-Lestienne C, Nibourel O, Boissel N, Terre C, Perot C, Eclache V, Gachard N, Tigaud I, Plessis G, Cuccuini W, Geffroy S, Villenet C, Figeac M, Leprêtre F, Renneville A, Cheok M, Soulier J, Dombret H, Preudhomme C; French ALFA group..

Am J Hematol. 2013 Apr;88(4):306-11. doi: 10.1002/ajh.23403. Epub 2013 Mar 5.

PubMed [citation]

PMID:: 23460398

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000718635.1

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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, SCV001362235.1

#	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.1005T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.3e-05 in 277190 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (8.3e-05 vs 0.00021), allowing no conclusion about variant significance. This variant has been reported in the literature in individuals affected with Neurofibromatosis Type 1 (Gasparini_1996, Bottillo_2007), without strong evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. Co-occurrences with other pathogenic variant have been reported (Bottillo_2007; NF1 c.476delC , p.Arg160Glyfs*5), providing supporting evidence for a benign role. In an in vitro mini gene assay, the variant was shown to abolish an expression of an alternative transcript lacking exon 7, however the clinical significance of this outcome is unclear (Bottillo_2007). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

#	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 Genetic Services Laboratory, University of Chicago, SCV002068089.1

#	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: Sep 29, 2024

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