ClinVar Genomic variation as it relates to human health
NM_000222.3(KIT):c.1727T>C (p.Leu576Pro)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000222.3(KIT):c.1727T>C (p.Leu576Pro)
Variation ID: 375919 Accession: VCV000375919.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 4q12 4: 55593661 (GRCh37) [ NCBI UCSC ] 4: 54727495 (GRCh38) [ 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 Nov 29, 2022 Sep 7, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000222.3:c.1727T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000213.1:p.Leu576Pro missense NM_001093772.2:c.1715T>C NP_001087241.1:p.Leu572Pro missense NM_001385284.1:c.1730T>C NP_001372213.1:p.Leu577Pro missense NM_001385285.1:c.1727T>C NP_001372214.1:p.Leu576Pro missense NM_001385286.1:c.1715T>C NP_001372215.1:p.Leu572Pro missense NM_001385288.1:c.1718T>C NP_001372217.1:p.Leu573Pro missense NM_001385290.1:c.1730T>C NP_001372219.1:p.Leu577Pro missense NM_001385292.1:c.1718T>C NP_001372221.1:p.Leu573Pro missense NC_000004.12:g.54727495T>C NC_000004.11:g.55593661T>C NG_007456.1:g.74501T>C LRG_307:g.74501T>C LRG_307t1:c.1727T>C LRG_307p1:p.Leu576Pro - Protein change
- L576P, L572P, L573P, L577P
- Other names
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- Canonical SPDI
- NC_000004.12:54727494:T:C
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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 |
2794 | 2820 |
Conditions - Germline
Condition
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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
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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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not provided (1) |
no classification provided
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Mar 10, 2016 | RCV000426967.2 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 14, 2015 | RCV000426330.2 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Jul 11, 2019 | RCV000433543.3 | |
Pathogenic (1) |
no assertion criteria provided
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Oct 2, 2014 | RCV000443552.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 7, 2021 | RCV002402118.2 |
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. |
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Likely pathogenic
(Jul 11, 2019)
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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: SCV001394325.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
This sequence change replaces leucine with proline at codon 576 of the KIT protein (p.Leu576Pro). The leucine residue is highly conserved and there is a … (more)
This sequence change replaces leucine with proline at codon 576 of the KIT protein (p.Leu576Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with GIST (PMID: 27771813), a family with multiple lentigines, GIST and esophageal stenosis (PMID: 23598963), and an individual with cutaneous mastocytosis and hyperpigmentation (Invitae). ClinVar contains an entry for this variant (Variation ID: 375919). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Pathogenic
(Sep 07, 2021)
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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: SCV002713705.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.L576P pathogenic mutation (also known as c.1727T>C), located in coding exon 11 of the KIT gene, results from a T to C substitution at … (more)
The p.L576P pathogenic mutation (also known as c.1727T>C), located in coding exon 11 of the KIT gene, results from a T to C substitution at nucleotide position 1727. The leucine at codon 576 is replaced by proline, an amino acid with similar properties. This alteration has been identified in multiple individuals with Gastrointestinal Stromal Tumors (GIST) and segregated with disease in at least one family (Ambry internal data; Neuhann TM et al. Am J Surg Pathol, 2013 Jun;37:898-905; Vale Rodrigues R et al. Fam Cancer, 2017 04;16:267-270; Piqueres-Zubiaurre T et al. Pediatr Dermatol, 2017 Jan;34:84-89). In one family, the alteration is assumed to be de novo in the proband who was affected with GIST after both unaffected parents were found to be wildtype (Vale Rodrigues R et al. Fam Cancer, 2017 04;16:267-270). Cells stably expressing this variant were able to survive without KIT ligand supporting the constitutive activation of the KIT pathway (Antonescu CR et al. Int J Cancer, 2007 Jul;121:257-64). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jul 14, 2015)
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no assertion criteria provided
Method: literature only
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Melanoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504189.1
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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Gastrointestinal stromal tumor
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504190.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Oct 02, 2014)
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no assertion criteria provided
Method: literature only
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Thymoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504191.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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not provided
(Mar 10, 2016)
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no classification provided
Method: literature only
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Non-small cell lung carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000504192.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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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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Familial Progressive Hyperpigmentation, Cutaneous Mastocytosis, and Gastrointestinal Stromal Tumor as Clinical Manifestations of Mutations in the c-KIT Receptor Gene. | Piqueres-Zubiaurre T | Pediatric dermatology | 2017 | PMID: 27981619 |
A case of multiple gastrointestinal stromal tumors caused by a germline KIT gene mutation (p.Leu576Pro). | Vale Rodrigues R | Familial cancer | 2017 | PMID: 27771813 |
Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors. | Schirosi L | Annals of oncology : official journal of the European Society for Medical Oncology | 2012 | PMID: 22357254 |
Sunitinib therapy for melanoma patients with KIT mutations. | Minor DR | Clinical cancer research : an official journal of the American Association for Cancer Research | 2012 | PMID: 22261812 |
Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. | Guo J | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21690468 |
KIT as a therapeutic target in metastatic melanoma. | Carvajal RD | JAMA | 2011 | PMID: 21642685 |
Anal mucosal melanoma with KIT-activating mutation and response to imatinib therapy--case report and review of the literature. | Satzger I | Dermatology (Basel, Switzerland) | 2010 | PMID: 19996579 |
Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. | Woodman SE | Molecular cancer therapeutics | 2009 | PMID: 19671763 |
KIT gene mutations and copy number in melanoma subtypes. | Beadling C | Clinical cancer research : an official journal of the American Association for Cancer Research | 2008 | PMID: 18980976 |
Mutational status of EGFR and KIT in thymoma and thymic carcinoma. | Yoh K | Lung cancer (Amsterdam, Netherlands) | 2008 | PMID: 18448188 |
L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. | Antonescu CR | International journal of cancer | 2007 | PMID: 17372901 |
Somatic activation of KIT in distinct subtypes of melanoma. | Curtin JA | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2006 | PMID: 16908931 |
An update on molecular genetics of gastrointestinal stromal tumours. | Tornillo L | Journal of clinical pathology | 2006 | PMID: 16731599 |
Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412. | Growney JD | Blood | 2005 | PMID: 15790786 |
Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours. | Hirota S | The Journal of pathology | 2001 | PMID: 11276010 |
Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. | Hirota S | Science (New York, N.Y.) | 1998 | PMID: 9438854 |
Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. | Kitayama H | Blood | 1995 | PMID: 7530509 |
http://docm.genome.wustl.edu/variants/ENST00000288135:c.1727T>C | - | - | - | - |
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Text-mined citations for rs121913513 ...
HelpRecord last updated Apr 15, 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.