VCV000041606.21 - ClinVar

NM_000222.3(KIT):c.910A>G (p.Thr304Ala)

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.

(9)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(1); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000222.3(KIT):c.910A>G (p.Thr304Ala)

Variation ID: 41606 Accession: VCV000041606.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4q12 4: 54703877 (GRCh38) [ NCBI UCSC ] 4: 55570043 (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	Apr 12, 2013	May 1, 2024	Jan 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000222.3:c.910A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000213.1:p.Thr304Ala	missense
NM_001093772.2:c.910A>G	NP_001087241.1:p.Thr304Ala	missense
NM_001385284.1:c.913A>G	NP_001372213.1:p.Thr305Ala	missense
NM_001385285.1:c.910A>G	NP_001372214.1:p.Thr304Ala	missense
NM_001385286.1:c.910A>G	NP_001372215.1:p.Thr304Ala	missense
NM_001385288.1:c.913A>G	NP_001372217.1:p.Thr305Ala	missense
NM_001385290.1:c.913A>G	NP_001372219.1:p.Thr305Ala	missense
NM_001385292.1:c.913A>G	NP_001372221.1:p.Thr305Ala	missense
NC_000004.12:g.54703877A>G
NC_000004.11:g.55570043A>G
NG_007456.1:g.50883A>G
LRG_307:g.50883A>G
LRG_307t1:c.910A>G	LRG_307p1:p.Thr304Ala

... more HGVS ... less HGVS

Protein change

T304A, T305A

Other names

Canonical SPDI

NC_000004.12:54703876:A:G

Functional
consequence

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

Global minor allele
frequency (GMAF)

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.

0.00020 (G)

Allele frequency

The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00008

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00020

The Genome Aggregation Database (gnomAD), exomes 0.00021

Links

ClinGen: CA215605

dbSNP: rs202052259

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.
KIT		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2881	2909

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	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	May 18, 2021	RCV001018858.6
Gastrointestinal stromal tumor	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 21, 2024	RCV001081377.15
Mastocytosis	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV001148078.5
Piebaldism	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2018	RCV001147190.5
Ovarian cancer	no classifications from unflagged records (1)	no classifications from unflagged records	Nov 3, 2023	RCV003153322.4
not provided	Uncertain significance (1)	no assertion criteria provided	Jul 13, 2012	RCV000034511.4

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.
Uncertain significance (May 18, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002536409.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The KIT c.910A>G (p.T304A) variant has not been reported in individuals with KIT-related cancer to our knowledge. This variant was observed in 56/19954 chromosomes in … (more) The KIT c.910A>G (p.T304A) variant has not been reported in individuals with KIT-related cancer to our knowledge. This variant was observed in 56/19954 chromosomes in the East Asian population, with no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 41606). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. Based on the current evidence available, this variant is interpreted as a variant of uncertain significance. (less)
Uncertain significance (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Piebaldism Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001307977.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Likely benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Gastrointestinal stromal tumor Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001308941.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Cutaneous mastocytosis Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001308942.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Uncertain significance (Jul 05, 2022)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Gastrointestinal stromal tumor Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV002584744.1 First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022	Comment: The KIT c.910A>G (p.Thr304Ala) missense change has a maximum frequency of 0.28% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a … (more) The KIT c.910A>G (p.Thr304Ala) missense change has a maximum frequency of 0.28% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with piebaldism who harbored a second missense variant in KIT however it was not known if the variants were on the same or opposite alleles (PMID: 25176472). To our knowledge, this variant has not been reported in individuals with gastrointestinal stromal tumor. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
Likely benign (Jan 21, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Gastrointestinal stromal tumor Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000560704.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024
Uncertain significance (May 21, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001180145.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 25176472 Comment: The p.T304A variant (also known as c.910A>G), located in coding exon 5 of the KIT gene, results from an A to G substitution at nucleotide … (more) The p.T304A variant (also known as c.910A>G), located in coding exon 5 of the KIT gene, results from an A to G substitution at nucleotide position 910. The threonine at codon 304 is replaced by alanine, an amino acid with similar properties. This alteration was seen in a patient with piebaldism who was also positive for another alteration in the KIT gene, p.E583D (Lee H et al. J. Dermatol. Sci., 2014 Oct;76:74-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
variant of unknown significance (Jul 13, 2012)	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043277.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Uncertain significance. Number of individuals with the variant: 1 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Likely pathogenic (Jan 01, 2022)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Ovarian cancer Affected status: yes Allele origin: germline	Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University Accession: SCV003843702.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

The KIT c.910A>G (p.Thr304Ala) missense change has a maximum frequency of 0.28% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with piebaldism who harbored a second missense variant in KIT however it was not known if the variants were on the same or opposite alleles (PMID: 25176472). To our knowledge, this variant has not been reported in individuals with gastrointestinal stromal tumor. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

Comment:

The p.T304A variant (also known as c.910A>G), located in coding exon 5 of the KIT gene, results from an A to G substitution at nucleotide position 910. The threonine at codon 304 is replaced by alanine, an amino acid with similar properties. This alteration was seen in a patient with piebaldism who was also positive for another alteration in the KIT gene, p.E583D (Lee H et al. J. Dermatol. Sci., 2014 Oct;76:74-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel mutations of KIT gene in two Korean patients: variegated shades of phenotypes in tyrosine kinase 1 domain.	Lee H	Journal of dermatological science	2014	PMID: 25176472

Text-mined citations for rs202052259 ...

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_000222.3(KIT):c.910A>G (p.Thr304Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs202052259 ...