ClinVar Genomic variation as it relates to human health
NM_001042492.3(NF1):c.3436G>A (p.Val1146Ile)
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.
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.
Uncertain significance(14); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001042492.3(NF1):c.3436G>A (p.Val1146Ile)
Variation ID: 141451 Accession: VCV000141451.37
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q11.2 17: 31232821 (GRCh38) [ NCBI UCSC ] 17: 29559839 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Sep 24, 2016 Feb 14, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001042492.3:c.3436G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035957.1:p.Val1146Ile missense NM_000267.3:c.3436G>A NP_000258.1:p.Val1146Ile missense NC_000017.11:g.31232821G>A NC_000017.10:g.29559839G>A NG_009018.1:g.142845G>A LRG_214:g.142845G>A LRG_214t1:c.3436G>A LRG_214p1:p.Val1146Ile LRG_214t2:c.3436G>A LRG_214p2:p.Val1146Ile - Protein change
- V1146I
- Other names
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- Canonical SPDI
- NC_000017.11:31232820:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Exome Aggregation Consortium (ExAC) 0.00011
The Genome Aggregation Database (gnomAD), exomes 0.00013
The Genome Aggregation Database (gnomAD) 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00019
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 | ||
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HI score
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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. |
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NF1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
13562 | 13971 |
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. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Oct 23, 2020 | RCV000129967.15 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
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Feb 1, 2024 | RCV000200527.35 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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May 23, 2019 | RCV000612512.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001125917.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001125918.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Apr 27, 2017 | RCV001125919.12 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 3, 2023 | RCV001594850.19 |
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. |
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Uncertain significance
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000822095.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Likely benign
(Dec 06, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000184791.5
First in ClinVar: Aug 06, 2014 Last updated: Mar 25, 2020 |
Comment:
Does not segregate with disease in family study (genes with incomplete penetrance);in silico models in agreement (benign);Other data supporting benign classification
Number of individuals with the variant: 1
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Uncertain significance
(Oct 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV001478982.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
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Likely benign
(Oct 30, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001829342.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 31159747, 15627836, 16138229, 23656349, 31891871)
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Uncertain significance
(Apr 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV002049586.1
First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022 |
Comment:
The NF1 c.3436G>A; p.Val1146Ile variant (rs201047812) is reported in the literature in individuals affected with neurofibromatosis type 1 or another unspecified cancer, but without clear … (more)
The NF1 c.3436G>A; p.Val1146Ile variant (rs201047812) is reported in the literature in individuals affected with neurofibromatosis type 1 or another unspecified cancer, but without clear association with disease (Trovo-Marqui 2005, Tsaousis 2019). This variant is also reported in ClinVar (Variation ID: 141451), and is found in the general population with an overall allele frequency of 0.012% (33/282760 alleles) in the Genome Aggregation Database. The valine at codon 1146 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.251). Due to limited information, the clinical significance of the p.Val1146Ile variant is uncertain at this time. References: Trovo-Marqui AB et al. High frequencies of plexiform neurofibromas, mental retardation, learning difficulties, and scoliosis in Brazilian patients with neurofibromatosis type 1. Braz J Med Biol Res. 2005 Sep;38(9):1441-7. PMID: 16138229. Tsaousis et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. PMID: 31159747 (less)
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Uncertain significance
(Aug 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Medical Genetics, University of Parma
Accession: SCV002567765.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
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Uncertain significance
(Jan 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579669.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: BP4
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Number of individuals with the variant: 1
Sex: female
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Uncertain significance
(Aug 11, 2016)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711646.2
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The p.Val1164Ile variant in NF1 has been reported in 3 individuals with Neurofib romatosis type 1 (NF1; Trovo 2004, Mendelian Genes). This variant has also … (more)
The p.Val1164Ile variant in NF1 has been reported in 3 individuals with Neurofib romatosis type 1 (NF1; Trovo 2004, Mendelian Genes). This variant has also been identified in 11/66714 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201047812). An additional amino a cid change at this position (p.Val1164 Phe) has been reported to occur de novo i n two individuals with NF1 (Mendelian Genes), suggesting that a change at this p osition may not be tolerated. However, valine (Val) at position 1146 is not cons erved in evolutionary distant species, with multiple fish species carrying an is oleucine (Ile) at this position, and raising the possibility that a change at th is position may be tolerated. Additional computational prediction tools suggest that the p.Val1146Ile variant may not impact the protein, though this informatio n is not predictive enough to rule out pathogenicity. In summary, due to conflic ting data, the clinical significance of the p.Val1146Ile variant is uncertain. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001285052.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis-Noonan syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001285051.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Café-au-lait macules with pulmonary stenosis
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001285054.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, familial spinal
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001285053.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(May 23, 2019)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001363373.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: NF1 c.3436G>A (p.Val1146Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: NF1 c.3436G>A (p.Val1146Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251366 control chromosomes, predominantly observed within the Latino subpopulation (at a frequency of 0.00023) and the in the European (Non-Finnish) subpopulation (at frequency of 0.00019) in the gnomAD database. The variant frequency in the Latino subpopulation is higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.00023 vs 0.00021), suggesting that the variant is might be benign. In addition, the variant occurs in certain European subpopulations with even higher frequencies (e.g. in the Bulgarians (0.0015), and in Southern Europeans (0.00026)) further supporting a benign role. The c.3436G>A variant has been reported in the literature in an individual affected with Neurofibromatosis Type 1, however these publications cited the variant as a polymorphism (Trovo_2004, Trovo-Marqui_2005). Therefore these reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. A co-occurrence with another pathogenic NF1 variant has been reported (NF1 c.3892C>T (p.Gln1298X) in an internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four classified the variant as VUS, while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
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Uncertain significance
(Oct 24, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002067551.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
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Likely benign
(Oct 23, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002527510.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Jul 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000839142.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
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Uncertain significance
(Feb 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222164.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00023 (8/35432 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for … (more)
The frequency of this variant in the general population, 0.00023 (8/35432 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in patients with Neurofibromatosis, type 1 (PMIDs: 23656349 (2014) and 16138229 (2005)) and breast cancer (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). The variant has been reported as a somatic finding in a glioma tumor sample (PMID: 31891871 (2020)). In addition, this variant has been reported in healthy control individuals (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Likely benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000254494.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Is There an Independent Role of TERT and NF1 in High Grade Gliomas? | Razis E | Translational oncology | 2020 | PMID: 31891871 |
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. | Tang CM | Oncotarget | 2016 | PMID: 27793025 |
A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. | van Minkelen R | Clinical genetics | 2014 | PMID: 23656349 |
High frequencies of plexiform neurofibromas, mental retardation, learning difficulties, and scoliosis in Brazilian patients with neurofibromatosis type 1. | Trovó-Marqui AB | Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas | 2005 | PMID: 16138229 |
Text-mined citations for rs201047812 ...
HelpRecord last updated Jun 02, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.