VCV000184523.19 - ClinVar

NM_001042492.3(NF1):c.1599C>G (p.Val533=)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001042492.3(NF1):c.1599C>G (p.Val533=)

Variation ID: 184523 Accession: VCV000184523.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q11.2 17: 31219076 (GRCh38) [ NCBI UCSC ] 17: 29546094 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 24, 2015	Sep 29, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001042492.3:c.1599C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001035957.1:p.Val533=	synonymous
NM_000267.3:c.1599C>G	NP_000258.1:p.Val533=	synonymous
NM_001128147.3:c.1599C>G	NP_001121619.1:p.Val533=	synonymous
NC_000017.11:g.31219076C>G
NC_000017.10:g.29546094C>G
NG_009018.1:g.129100C>G
LRG_214:g.129100C>G
LRG_214t1:c.1599C>G	LRG_214p1:p.Val533=
LRG_214t2:c.1599C>G	LRG_214p2:p.Val533=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000017.11:31219075:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00008

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00013

The Genome Aggregation Database (gnomAD), exomes 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00017

Links

ClinGen: CA189193 dbSNP: rs369458366 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NF1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	14135	14574

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Sep 5, 2023	RCV000163792.4
Neurofibromatosis, type 1	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000206359.18
not specified	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Oct 18, 2023	RCV000606948.4
not provided	Likely benign (1)	criteria provided, multiple submitters, no conflicts	May 17, 2021	RCV001706077.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781918.1 First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018
Likely benign (Oct 08, 2020)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001442756.1 First in ClinVar: Nov 12, 2020 Last updated: Nov 12, 2020	Publications: PubMed (4) PubMed: 10678181‚ 23460398‚ 29872168‚ 27069254
Likely benign (Nov 21, 2014)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015)) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000214373.4 First in ClinVar: Mar 24, 2015 Last updated: Mar 24, 2015	Comment: This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more) This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Number of individuals with the variant: 1
Likely benign (Oct 26, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV001479199.1 First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021
Likely benign (May 17, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000726815.2 First in ClinVar: Apr 09, 2018 Last updated: Sep 26, 2021	Comment: This variant is associated with the following publications: (PMID: 27534895)
Likely benign (Sep 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV004228107.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024
benign (Oct 18, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004222156.2 First in ClinVar: Jan 06, 2024 Last updated: Sep 29, 2024	Comment: The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools … (more) The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing. This nucleotide position exhibits low evolutionary conservation. (less)
Benign (Jun 10, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002527410.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurofibromatosis, type 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002560472.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neurofibromatosis, type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000260079.10 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024

Comment:

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing. This nucleotide position exhibits low evolutionary conservation.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome.	Eisfeld AK	Leukemia	2018	PMID: 29872168
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.	Arber DA	Blood	2016	PMID: 27069254
Neurofibromatosis-1 gene deletions and mutations in de novo adult acute myeloid leukemia.	Boudry-Labis E	American journal of hematology	2013	PMID: 23460398
Nf1 and Gmcsf interact in myeloid leukemogenesis.	Birnbaum RA	Molecular cell	2000	PMID: 10678181

Text-mined citations for rs369458366 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001042492.3(NF1):c.1599C>G (p.Val533=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs369458366 ...