ClinVar Genomic variation as it relates to human health
NM_000222.3(KIT):c.2447A>T (p.Asp816Val)
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.
Pathogenic(1); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000222.3(KIT):c.2447A>T (p.Asp816Val)
Variation ID: 13852 Accession: VCV000013852.47
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q12 4: 54733155 (GRCh38) [ NCBI UCSC ] 4: 55599321 (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 Mar 8, 2017 May 1, 2024 Nov 1, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000222.3:c.2447A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000213.1:p.Asp816Val missense NM_001093772.2:c.2435A>T NP_001087241.1:p.Asp812Val missense NM_001385284.1:c.2450A>T NP_001372213.1:p.Asp817Val missense NM_001385285.1:c.2444A>T NP_001372214.1:p.Asp815Val missense NM_001385286.1:c.2432A>T NP_001372215.1:p.Asp811Val missense NM_001385288.1:c.2438A>T NP_001372217.1:p.Asp813Val missense NM_001385290.1:c.2447A>T NP_001372219.1:p.Asp816Val missense NM_001385292.1:c.2435A>T NP_001372221.1:p.Asp812Val missense NC_000004.12:g.54733155A>T NC_000004.11:g.55599321A>T NG_007456.1:g.80161A>T LRG_307:g.80161A>T LRG_307t1:c.2447A>T LRG_307p1:p.Asp816Val P10721:p.Asp816Val - Protein change
- D816V, D812V, D811V, D813V, D815V, D817V
- Other names
- -
- Canonical SPDI
- NC_000004.12:54733154:A:T
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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.
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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
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. |
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KIT | - | - |
GRCh38 GRCh37 |
2837 | 2863 |
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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Likely pathogenic (1) |
no assertion criteria provided
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Jul 14, 2015 | RCV000014864.31 | |
Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000443179.8 | |
Pathogenic (1) |
no assertion criteria provided
|
Mar 10, 2016 | RCV000444150.8 | |
other (1) |
no assertion criteria provided
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May 1, 2016 | RCV000505554.8 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 15, 2001 | RCV000656673.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 24, 2014 | RCV001269832.9 | |
Uncertain significance (2) |
criteria provided, single submitter
|
Nov 1, 2022 | RCV000431704.15 | |
Pathogenic (1) |
no assertion criteria provided
|
Aug 15, 2001 | RCV000656675.15 | |
Pathogenic (1) |
no assertion criteria provided
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Aug 15, 2001 | RCV000656674.15 | |
Uncertain significance (2) |
criteria provided, single submitter
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Aug 31, 2021 | RCV000656676.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 12, 2020 | RCV002453261.9 | |
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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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Pathogenic
(Nov 24, 2014)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001450124.1
First in ClinVar: Dec 11, 2020 Last updated: Dec 11, 2020 |
Number of individuals with the variant: 2
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Uncertain significance
(Nov 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Gastrointestinal stromal tumor
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000630471.6
First in ClinVar: Dec 26, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 816 of the KIT protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 816 of the KIT protein (p.Asp816Val). This variant is not present in population databases (gnomAD no frequency). This variant is the most common somatic change in mastocytosis (PMID: 27777718, 26158763). While this variant has been reported in the literature, it has not been reported in the germline of individuals with KIT-related conditions. ClinVar contains an entry for this variant (Variation ID: 13852). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this variant leads to a gain-of-function of the KIT protein, causing ligand-independent signaling activation as well as oncogenic transformation in vitro (PMID: 27777718, 26158763). In addition, transgenic mice expressing this variant (D816V) show abnormal mast cell proliferation and recapitulate human mastocytosis (PMID: 16352739). However, the clinical significance of the functional impact in the germline is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 12, 2020)
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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: SCV002737988.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.D816V variant (also known as c.2447A>T), located in coding exon 17 of the KIT gene, results from an A to T substitution at nucleotide … (more)
The p.D816V variant (also known as c.2447A>T), located in coding exon 17 of the KIT gene, results from an A to T substitution at nucleotide position 2447. The aspartic acid at codon 816 is replaced by valine, an amino acid with highly dissimilar properties. This variant is the most common somatic alteration reported in adults with acquired mastocytosis (Arock M et al. Leukemia 2015 Jun;29(6):1223-32; Orfao A et al. Br. J. Haematol. 2007 Jul;138(1):12-30; Nagata H et al. Proc. Natl. Acad. Sci. U.S.A. 1995 Nov;92(23):10560-4; Baird J et al. Curr Hematol Malig Rep 2018 10;13(5):407-416). Functional studies have demonstrated that p.D816V leads to constitutive activation of KIT (Foster R et al. J. Mol. Graph. Model. 2004 Oct;23(2):139-52; Nagata et al). To our knowledge, p.D816V has not yet been identified as a germline alteration and has not been established to confer increased risk of familial gastrointestinal stromal tumors (GIST). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration in germline carriers remains unclear. (less)
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Uncertain significance
(Aug 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cutaneous mastocytosis
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512760.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS3 supporting, PM2 moderate, PP3 supporting
Geographic origin: Brazil
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Likely pathogenic
(Jul 14, 2015)
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no assertion criteria provided
Method: literature only
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Mast cell leukemia
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504209.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Mar 10, 2016)
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no assertion criteria provided
Method: literature only
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Acute myeloid leukemia
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504208.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Hematologic neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504211.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(Dec 26, 2014)
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no assertion criteria provided
Method: literature only
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Gastrointestinal stromal tumor
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504210.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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other
2: Mutations in members of targetable cancer pathways, gene families, or functional groups, regardless of tumor type;
(May 01, 2016)
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no assertion criteria provided
Method: clinical testing
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DYSGERMINOMA
SOMATIC:c2996_dysgerminoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Donald Williams Parsons Laboratory, Baylor College of Medicine
Additional submitter:
Donald Williams Parsons Laboratory, Baylor College of Medicine
Study: CSER-BASIC3
Accession: SCV000599929.1 First in ClinVar: Sep 26, 2017 Last updated: Sep 26, 2017 |
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Pathogenic
(Aug 15, 2001)
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no assertion criteria provided
Method: literature only
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MASTOCYTOSIS WITH ASSOCIATED HEMATOLOGIC DISORDER, SOMATIC
Affected status: not provided
Allele origin:
somatic
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OMIM
Accession: SCV000778808.5
First in ClinVar: Jun 30, 2018 Last updated: Mar 10, 2024 |
Comment on evidence:
In a human mast cell leukemia (see 154800) cell line (HMC-1), Furitsu et al. (1993) found 2 point mutations in KIT that resulted in val560-to-gly … (more)
In a human mast cell leukemia (see 154800) cell line (HMC-1), Furitsu et al. (1993) found 2 point mutations in KIT that resulted in val560-to-gly and asp816-to-val (D816V) substitutions in the cytoplasmic domain. Amino acid sequences in the regions of the 2 mutations are completely conserved in all of mouse, rat, and human KIT. To determine the causal role of these mutations in constitutive activation, murine Kit mutants encoding gly559 and/or val814, corresponding to human gly560 and/or val816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line. In the transfected cells, both KitR (gly559, val814) and KitR (val814) were abundantly phosphorylated on tyrosine and activated in immune complex kinase reaction in the absence of SCF, whereas tyrosine phosphorylation and activation of KitR (gly559) or wildtype KitR was modest or little, respectively. Furitsu et al. (1993) suggested that the D816V mutation plays a major role in the constitutive activation of c-Kit product in HMC-1 cells, while the V560G mutation plays a minor role. In 4 patients with mastocytosis associated with a hematologic disorder (see 154800) with predominantly myelodysplastic features, Nagata et al. (1995) identified a 2468A-T transversion in KIT mRNA, resulting in the D816V substitution. The presence of the mutation in genomic DNA from PBMCs was established in the 1 patient studied. Identical or similar amino acid substitutions in mast cell lines result in ligand-independent autophosphorylation of KIT (mast/stem cell growth factor receptor). The mutation was not identified in 5 patients with other forms of mastocytosis, including 3 with indolent mastocytosis, 1 with aggressive mastocytosis, and 1 with a solitary mastocytoma, or in 1 patient with chronic myelomonocytic leukemia (CMML; see 607785), or in 67 controls. Longley et al. (1996) found heterozygosity for the D816V substitution in mast cells from a patient with urticaria pigmentosa with aggressive systemic mastocytosis with massive splenic involvement. They were able to demonstrate expression of KIT in mast cells of both skin and spleen. This was said to be the first in situ demonstration of an activating KIT mutation in neoplastic cells. That a somatic mutation was involved was indicated by the fact that ectodermally-derived epithelial cells of the buccal mucosa and non-mast cell leukocytes did not show the mutation. To determine whether the D816V mutation is associated with identifiable clinical patterns and prognosis of mastocytosis, Worobec et al. (1998) screened 65 patients with systemic mastocytosis for the presence of the mutation in peripheral blood mononuclear cells. They found this mutation in 16 cases (25%): 15 adults and 1 infant, but not in any children with mastocytosis. Patients with the mutation manifested a more severe disease pattern and commonly had osteosclerotic bone involvement as well as immunoglobulin dysregulation and peripheral blood abnormalities. Pedigree analysis of 3 families provided evidence that the mutation was somatic. Longley et al. (1999) found the D816V mutation in 11 cases of adult sporadic mastocytosis. In 3 of the patients the disorder presented in adulthood with progressive urticaria pigmentosa with systemic involvement. The 8 other cases presented as sporadic, slowly progressive, or persistent adult urticaria pigmentosa without systemic involvement. Thus, all patients with adult sporadic mastocytosis had somatic KIT mutations in codon 816 causing spontaneous activation of mast cell growth factor receptor. The D816V substitution was also detected in 1 pediatric patient with progressive cutaneous disease without systemic involvement. Fritsche-Polanz et al. (2001) studied 12 patients with systemic mastocytosis. All 11 patients with systemic indolent mastocytosis tested positive for the 2468A-T nucleotide substitution in KIT, resulting in the D816V substitution. In contrast, no mutation was identified in the 1 case of aggressive mastocytosis. Taylor et al. (2001) demonstrated that the D816V mutation enhances chemotaxis of CD117(+) cells, offering one explanation for increased mast cells derived from CD34(+)CD117(+) mast cell precursors observed in tissues of patients with mastocytosis. In 6 of 12 patients with systemic mastocytosis who had mutations in the TET2 gene (612830), Tefferi et al. (2009) also detected the D816V mutation in KIT. The authors concluded that TET2 mutations are frequent in systemic mastocytosis and segregate with the D816V mutation in KIT. In cutaneous biopsies from 18 (36%) of 50 children with mastocytosis, Bodemer et al. (2010) identified heterozygosity for the D816V mutation in KIT. Two of the patients represented familial cases. (less)
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Pathogenic
(Aug 15, 2001)
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no assertion criteria provided
Method: literature only
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MASTOCYTOSIS, SYSTEMIC, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000778809.5
First in ClinVar: Jun 30, 2018 Last updated: Mar 10, 2024 |
Comment on evidence:
In a human mast cell leukemia (see 154800) cell line (HMC-1), Furitsu et al. (1993) found 2 point mutations in KIT that resulted in val560-to-gly … (more)
In a human mast cell leukemia (see 154800) cell line (HMC-1), Furitsu et al. (1993) found 2 point mutations in KIT that resulted in val560-to-gly and asp816-to-val (D816V) substitutions in the cytoplasmic domain. Amino acid sequences in the regions of the 2 mutations are completely conserved in all of mouse, rat, and human KIT. To determine the causal role of these mutations in constitutive activation, murine Kit mutants encoding gly559 and/or val814, corresponding to human gly560 and/or val816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line. In the transfected cells, both KitR (gly559, val814) and KitR (val814) were abundantly phosphorylated on tyrosine and activated in immune complex kinase reaction in the absence of SCF, whereas tyrosine phosphorylation and activation of KitR (gly559) or wildtype KitR was modest or little, respectively. Furitsu et al. (1993) suggested that the D816V mutation plays a major role in the constitutive activation of c-Kit product in HMC-1 cells, while the V560G mutation plays a minor role. In 4 patients with mastocytosis associated with a hematologic disorder (see 154800) with predominantly myelodysplastic features, Nagata et al. (1995) identified a 2468A-T transversion in KIT mRNA, resulting in the D816V substitution. The presence of the mutation in genomic DNA from PBMCs was established in the 1 patient studied. Identical or similar amino acid substitutions in mast cell lines result in ligand-independent autophosphorylation of KIT (mast/stem cell growth factor receptor). The mutation was not identified in 5 patients with other forms of mastocytosis, including 3 with indolent mastocytosis, 1 with aggressive mastocytosis, and 1 with a solitary mastocytoma, or in 1 patient with chronic myelomonocytic leukemia (CMML; see 607785), or in 67 controls. Longley et al. (1996) found heterozygosity for the D816V substitution in mast cells from a patient with urticaria pigmentosa with aggressive systemic mastocytosis with massive splenic involvement. They were able to demonstrate expression of KIT in mast cells of both skin and spleen. This was said to be the first in situ demonstration of an activating KIT mutation in neoplastic cells. That a somatic mutation was involved was indicated by the fact that ectodermally-derived epithelial cells of the buccal mucosa and non-mast cell leukocytes did not show the mutation. To determine whether the D816V mutation is associated with identifiable clinical patterns and prognosis of mastocytosis, Worobec et al. (1998) screened 65 patients with systemic mastocytosis for the presence of the mutation in peripheral blood mononuclear cells. They found this mutation in 16 cases (25%): 15 adults and 1 infant, but not in any children with mastocytosis. Patients with the mutation manifested a more severe disease pattern and commonly had osteosclerotic bone involvement as well as immunoglobulin dysregulation and peripheral blood abnormalities. Pedigree analysis of 3 families provided evidence that the mutation was somatic. Longley et al. (1999) found the D816V mutation in 11 cases of adult sporadic mastocytosis. In 3 of the patients the disorder presented in adulthood with progressive urticaria pigmentosa with systemic involvement. The 8 other cases presented as sporadic, slowly progressive, or persistent adult urticaria pigmentosa without systemic involvement. Thus, all patients with adult sporadic mastocytosis had somatic KIT mutations in codon 816 causing spontaneous activation of mast cell growth factor receptor. The D816V substitution was also detected in 1 pediatric patient with progressive cutaneous disease without systemic involvement. Fritsche-Polanz et al. (2001) studied 12 patients with systemic mastocytosis. All 11 patients with systemic indolent mastocytosis tested positive for the 2468A-T nucleotide substitution in KIT, resulting in the D816V substitution. In contrast, no mutation was identified in the 1 case of aggressive mastocytosis. Taylor et al. (2001) demonstrated that the D816V mutation enhances chemotaxis of CD117(+) cells, offering one explanation for increased mast cells derived from CD34(+)CD117(+) mast cell precursors observed in tissues of patients with mastocytosis. In 6 of 12 patients with systemic mastocytosis who had mutations in the TET2 gene (612830), Tefferi et al. (2009) also detected the D816V mutation in KIT. The authors concluded that TET2 mutations are frequent in systemic mastocytosis and segregate with the D816V mutation in KIT. In cutaneous biopsies from 18 (36%) of 50 children with mastocytosis, Bodemer et al. (2010) identified heterozygosity for the D816V mutation in KIT. Two of the patients represented familial cases. (less)
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Pathogenic
(Aug 15, 2001)
|
no assertion criteria provided
Method: literature only
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MAST CELL LEUKEMIA, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000035119.6
First in ClinVar: Apr 04, 2013 Last updated: Mar 10, 2024 |
Comment on evidence:
In a human mast cell leukemia (see 154800) cell line (HMC-1), Furitsu et al. (1993) found 2 point mutations in KIT that resulted in val560-to-gly … (more)
In a human mast cell leukemia (see 154800) cell line (HMC-1), Furitsu et al. (1993) found 2 point mutations in KIT that resulted in val560-to-gly and asp816-to-val (D816V) substitutions in the cytoplasmic domain. Amino acid sequences in the regions of the 2 mutations are completely conserved in all of mouse, rat, and human KIT. To determine the causal role of these mutations in constitutive activation, murine Kit mutants encoding gly559 and/or val814, corresponding to human gly560 and/or val816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line. In the transfected cells, both KitR (gly559, val814) and KitR (val814) were abundantly phosphorylated on tyrosine and activated in immune complex kinase reaction in the absence of SCF, whereas tyrosine phosphorylation and activation of KitR (gly559) or wildtype KitR was modest or little, respectively. Furitsu et al. (1993) suggested that the D816V mutation plays a major role in the constitutive activation of c-Kit product in HMC-1 cells, while the V560G mutation plays a minor role. In 4 patients with mastocytosis associated with a hematologic disorder (see 154800) with predominantly myelodysplastic features, Nagata et al. (1995) identified a 2468A-T transversion in KIT mRNA, resulting in the D816V substitution. The presence of the mutation in genomic DNA from PBMCs was established in the 1 patient studied. Identical or similar amino acid substitutions in mast cell lines result in ligand-independent autophosphorylation of KIT (mast/stem cell growth factor receptor). The mutation was not identified in 5 patients with other forms of mastocytosis, including 3 with indolent mastocytosis, 1 with aggressive mastocytosis, and 1 with a solitary mastocytoma, or in 1 patient with chronic myelomonocytic leukemia (CMML; see 607785), or in 67 controls. Longley et al. (1996) found heterozygosity for the D816V substitution in mast cells from a patient with urticaria pigmentosa with aggressive systemic mastocytosis with massive splenic involvement. They were able to demonstrate expression of KIT in mast cells of both skin and spleen. This was said to be the first in situ demonstration of an activating KIT mutation in neoplastic cells. That a somatic mutation was involved was indicated by the fact that ectodermally-derived epithelial cells of the buccal mucosa and non-mast cell leukocytes did not show the mutation. To determine whether the D816V mutation is associated with identifiable clinical patterns and prognosis of mastocytosis, Worobec et al. (1998) screened 65 patients with systemic mastocytosis for the presence of the mutation in peripheral blood mononuclear cells. They found this mutation in 16 cases (25%): 15 adults and 1 infant, but not in any children with mastocytosis. Patients with the mutation manifested a more severe disease pattern and commonly had osteosclerotic bone involvement as well as immunoglobulin dysregulation and peripheral blood abnormalities. Pedigree analysis of 3 families provided evidence that the mutation was somatic. Longley et al. (1999) found the D816V mutation in 11 cases of adult sporadic mastocytosis. In 3 of the patients the disorder presented in adulthood with progressive urticaria pigmentosa with systemic involvement. The 8 other cases presented as sporadic, slowly progressive, or persistent adult urticaria pigmentosa without systemic involvement. Thus, all patients with adult sporadic mastocytosis had somatic KIT mutations in codon 816 causing spontaneous activation of mast cell growth factor receptor. The D816V substitution was also detected in 1 pediatric patient with progressive cutaneous disease without systemic involvement. Fritsche-Polanz et al. (2001) studied 12 patients with systemic mastocytosis. All 11 patients with systemic indolent mastocytosis tested positive for the 2468A-T nucleotide substitution in KIT, resulting in the D816V substitution. In contrast, no mutation was identified in the 1 case of aggressive mastocytosis. Taylor et al. (2001) demonstrated that the D816V mutation enhances chemotaxis of CD117(+) cells, offering one explanation for increased mast cells derived from CD34(+)CD117(+) mast cell precursors observed in tissues of patients with mastocytosis. In 6 of 12 patients with systemic mastocytosis who had mutations in the TET2 gene (612830), Tefferi et al. (2009) also detected the D816V mutation in KIT. The authors concluded that TET2 mutations are frequent in systemic mastocytosis and segregate with the D816V mutation in KIT. In cutaneous biopsies from 18 (36%) of 50 children with mastocytosis, Bodemer et al. (2010) identified heterozygosity for the D816V mutation in KIT. Two of the patients represented familial cases. (less)
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Pathogenic
(Aug 15, 2001)
|
no assertion criteria provided
Method: literature only
|
MASTOCYTOSIS, CUTANEOUS
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000778810.5
First in ClinVar: Jun 30, 2018 Last updated: Mar 10, 2024 |
Comment on evidence:
In a human mast cell leukemia (see 154800) cell line (HMC-1), Furitsu et al. (1993) found 2 point mutations in KIT that resulted in val560-to-gly … (more)
In a human mast cell leukemia (see 154800) cell line (HMC-1), Furitsu et al. (1993) found 2 point mutations in KIT that resulted in val560-to-gly and asp816-to-val (D816V) substitutions in the cytoplasmic domain. Amino acid sequences in the regions of the 2 mutations are completely conserved in all of mouse, rat, and human KIT. To determine the causal role of these mutations in constitutive activation, murine Kit mutants encoding gly559 and/or val814, corresponding to human gly560 and/or val816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line. In the transfected cells, both KitR (gly559, val814) and KitR (val814) were abundantly phosphorylated on tyrosine and activated in immune complex kinase reaction in the absence of SCF, whereas tyrosine phosphorylation and activation of KitR (gly559) or wildtype KitR was modest or little, respectively. Furitsu et al. (1993) suggested that the D816V mutation plays a major role in the constitutive activation of c-Kit product in HMC-1 cells, while the V560G mutation plays a minor role. In 4 patients with mastocytosis associated with a hematologic disorder (see 154800) with predominantly myelodysplastic features, Nagata et al. (1995) identified a 2468A-T transversion in KIT mRNA, resulting in the D816V substitution. The presence of the mutation in genomic DNA from PBMCs was established in the 1 patient studied. Identical or similar amino acid substitutions in mast cell lines result in ligand-independent autophosphorylation of KIT (mast/stem cell growth factor receptor). The mutation was not identified in 5 patients with other forms of mastocytosis, including 3 with indolent mastocytosis, 1 with aggressive mastocytosis, and 1 with a solitary mastocytoma, or in 1 patient with chronic myelomonocytic leukemia (CMML; see 607785), or in 67 controls. Longley et al. (1996) found heterozygosity for the D816V substitution in mast cells from a patient with urticaria pigmentosa with aggressive systemic mastocytosis with massive splenic involvement. They were able to demonstrate expression of KIT in mast cells of both skin and spleen. This was said to be the first in situ demonstration of an activating KIT mutation in neoplastic cells. That a somatic mutation was involved was indicated by the fact that ectodermally-derived epithelial cells of the buccal mucosa and non-mast cell leukocytes did not show the mutation. To determine whether the D816V mutation is associated with identifiable clinical patterns and prognosis of mastocytosis, Worobec et al. (1998) screened 65 patients with systemic mastocytosis for the presence of the mutation in peripheral blood mononuclear cells. They found this mutation in 16 cases (25%): 15 adults and 1 infant, but not in any children with mastocytosis. Patients with the mutation manifested a more severe disease pattern and commonly had osteosclerotic bone involvement as well as immunoglobulin dysregulation and peripheral blood abnormalities. Pedigree analysis of 3 families provided evidence that the mutation was somatic. Longley et al. (1999) found the D816V mutation in 11 cases of adult sporadic mastocytosis. In 3 of the patients the disorder presented in adulthood with progressive urticaria pigmentosa with systemic involvement. The 8 other cases presented as sporadic, slowly progressive, or persistent adult urticaria pigmentosa without systemic involvement. Thus, all patients with adult sporadic mastocytosis had somatic KIT mutations in codon 816 causing spontaneous activation of mast cell growth factor receptor. The D816V substitution was also detected in 1 pediatric patient with progressive cutaneous disease without systemic involvement. Fritsche-Polanz et al. (2001) studied 12 patients with systemic mastocytosis. All 11 patients with systemic indolent mastocytosis tested positive for the 2468A-T nucleotide substitution in KIT, resulting in the D816V substitution. In contrast, no mutation was identified in the 1 case of aggressive mastocytosis. Taylor et al. (2001) demonstrated that the D816V mutation enhances chemotaxis of CD117(+) cells, offering one explanation for increased mast cells derived from CD34(+)CD117(+) mast cell precursors observed in tissues of patients with mastocytosis. In 6 of 12 patients with systemic mastocytosis who had mutations in the TET2 gene (612830), Tefferi et al. (2009) also detected the D816V mutation in KIT. The authors concluded that TET2 mutations are frequent in systemic mastocytosis and segregate with the D816V mutation in KIT. In cutaneous biopsies from 18 (36%) of 50 children with mastocytosis, Bodemer et al. (2010) identified heterozygosity for the D816V mutation in KIT. Two of the patients represented familial cases. (less)
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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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Germline mutations of KIT in gastrointestinal stromal tumor (GIST) and mastocytosis. | Ke H | Cell & bioscience | 2016 | PMID: 27777718 |
Mastocytosis: a mutated KIT receptor induced myeloproliferative disorder. | Chatterjee A | Oncotarget | 2015 | PMID: 26158763 |
Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
Hidden mastocytosis in acute myeloid leukemia with t(8;21)(q22;q22). | Johnson RC | American journal of clinical pathology | 2013 | PMID: 24045550 |
The role of kinase inhibitors in the treatment of patients with acute myeloid leukemia. | Smith CC | American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting | 2013 | PMID: 23714533 |
Secondary c-Kit mutations confer acquired resistance to RTK inhibitors in c-Kit mutant melanoma cells. | Todd JR | Pigment cell & melanoma research | 2013 | PMID: 23582185 |
Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. | Smith CC | Nature | 2012 | PMID: 22504184 |
Novel, activating KIT-N822I mutation in familial cutaneous mastocytosis. | Wasag B | Experimental hematology | 2011 | PMID: 21689725 |
Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. | Bodemer C | The Journal of investigative dermatology | 2010 | PMID: 19865100 |
Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. | Tefferi A | Leukemia | 2009 | PMID: 19262599 |
KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. | Gajiwala KS | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19164557 |
Chemotherapy and dasatinib induce long-term hematologic and molecular remission in systemic mastocytosis with acute myeloid leukemia with KIT D816V. | Ustun C | Leukemia research | 2009 | PMID: 18986703 |
Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT. | Gleixner KV | Haematologica | 2007 | PMID: 18024392 |
Juxtamembrane-type c-kit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation. | Nakagomi N | Laboratory investigation; a journal of technical methods and pathology | 2007 | PMID: 17259998 |
EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. | Pan J | Blood | 2007 | PMID: 16912224 |
An update on molecular genetics of gastrointestinal stromal tumours. | Tornillo L | Journal of clinical pathology | 2006 | PMID: 16731599 |
Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. | Cairoli R | Blood | 2006 | PMID: 16384925 |
Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. | Gotlib J | Blood | 2005 | PMID: 15972446 |
The Kit-activating mutation D816V enhances stem cell factor--dependent chemotaxis. | Taylor ML | Blood | 2001 | PMID: 11493470 |
Mutation analysis of C-KIT in patients with myelodysplastic syndromes without mastocytosis and cases of systemic mastocytosis. | Fritsche-Polanz R | British journal of haematology | 2001 | PMID: 11380399 |
Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. | Longley BJ Jr | Proceedings of the National Academy of Sciences of the United States of America | 1999 | PMID: 9990072 |
Clinical correlates of the presence of the Asp816Val c-kit mutation in the peripheral blood mononuclear cells of patients with mastocytosis. | Worobec AS | Cancer | 1998 | PMID: 9827716 |
Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. | Longley BJ | Nature genetics | 1996 | PMID: 8589724 |
Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. | Nagata H | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7479840 |
Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. | Furitsu T | The Journal of clinical investigation | 1993 | PMID: 7691885 |
http://docm.genome.wustl.edu/variants/ENST00000288135:c.2447A>T | - | - | - | - |
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Text-mined citations for rs121913507 ...
HelpRecord last updated May 01, 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.