ClinVar Miner

Submissions for variant NM_000222.2(KIT):c.2447A>T (p.Asp816Val) (rs121913507)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000431704 SCV000630471 uncertain significance Gastrointestinal stroma tumor 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 816 of the KIT protein (p.Asp816Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC 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 disease. ClinVar contains an entry for this variant (Variation ID: 13852). 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, this is a rare missense change that is associated with the pathogenesis of mastocytosis, and has been shown to affect protein function. However, in the absence of observations in the germline of individuals with inherited KIT-related disease, this variant has been classified as Variant of Uncertain Significance.
OMIM RCV000656673 SCV000035119 pathogenic MAST CELL LEUKEMIA, SOMATIC 2001-08-15 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444150 SCV000504208 pathogenic Acute myeloid leukemia 2016-03-10 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000014864 SCV000504209 likely pathogenic Mast cell leukemia 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431704 SCV000504210 likely pathogenic Gastrointestinal stroma tumor 2014-12-26 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443179 SCV000504211 likely pathogenic Hematologic neoplasm 2016-05-13 no assertion criteria provided literature only
Donald Williams Parsons Laboratory,Baylor College of Medicine RCV000505554 SCV000599929 other Dysgerminoma 2016-05-01 no assertion criteria provided clinical testing
OMIM RCV000656674 SCV000778808 pathogenic MASTOCYTOSIS WITH ASSOCIATED HEMATOLOGIC DISORDER, SOMATIC 2001-08-15 no assertion criteria provided literature only
OMIM RCV000656675 SCV000778809 pathogenic MASTOCYTOSIS, SYSTEMIC, SOMATIC 2001-08-15 no assertion criteria provided literature only
OMIM RCV000656676 SCV000778810 pathogenic Cutaneous mastocytosis 2001-08-15 no assertion criteria provided literature only

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