VCV000097006.3 - ClinVar

NM_004343.3(CALR):c.1092_1143del52 (p.Leu367Thrfs)

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.

(3)

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

criteria provided, single submitter

Somatic

Clinical impact

The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate somatic clinical impact 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.

Tier I (Strong) for Essential thrombocythemia

+lower levels of evidence for Acute myeloid leukemia

no assertion criteria provided

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity 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

no assertion criteria provided

Variant Details

Identifiers

NM_004343.3(CALR):c.1092_1143del52 (p.Leu367Thrfs)

Variation ID: 97006 Accession: VCV000097006.3

Type and length

Deletion, 52 bp

Location

Cytogenetic: 19p13.13 19: 12943751-12943802 (GRCh38) [ NCBI UCSC ] 19: 13054565-13054616 (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	May 5, 2014	Dec 31, 2022	Feb 10, 2022
Somatic - Clinical impact	Mar 5, 2024	Mar 5, 2024	Jan 24, 2024
Somatic - Oncogenicity	Mar 5, 2024	Mar 5, 2024	Jan 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004343.4:c.1099_1150del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004334.1:p.Leu367fs	frameshift
NM_004343.3:c.1092_1143del52
NC_000019.10:g.12943758_12943809del
NC_000019.9:g.13054572_13054623del
NG_029662.1:g.10159_10210del
LRG_828:g.10159_10210del

... more HGVS ... less HGVS

Protein change

L367fs

Other names

Canonical SPDI

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

Global minor allele frequency (GMAF) Help 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA149708 dbVar: nssv3761626 dbVar: nsv1067850 OMIM: 109091.0001 dbSNP: rs1555760738 VarSome

Comment on variant

52-nt deletion from exon 9 of CALR.

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.
CALR		-	-	GRCh38 GRCh37	22	73

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.
Primary myelofibrosis	Pathogenic (1)	no assertion criteria provided	Dec 19, 2013	RCV000083256.5
Thrombocythemia 1	Pathogenic (1)	no assertion criteria provided	Dec 19, 2013	RCV000083257.5
Primary myelofibrosis Thrombocythemia 1	Pathogenic (1)	criteria provided, single submitter	Feb 10, 2022	RCV002498437.1

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.
Pathogenic (Feb 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombocythemia 1 Primary myelofibrosis Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002812646.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Dec 19, 2013)	no assertion criteria provided Method: literature only	MYELOFIBROSIS, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000115335.2 First in ClinVar: Feb 11, 2014 Last updated: May 05, 2014	Publications: PubMed (2) PubMed: 24325356‚ 24325359 Comment on evidence: Klampfl et al. (2013) and Nangalia et al. (2013) identified a somatic 52-bp deletion in exon 9 of the CALR gene (1092_1143del) in patients with … (more) Klampfl et al. (2013) and Nangalia et al. (2013) identified a somatic 52-bp deletion in exon 9 of the CALR gene (1092_1143del) in patients with myeloproliferative neoplasms, including myelofibrosis (254450) and essential thrombocythemia (see 187950). CALR mutations and JAK2 and MPL mutations were mutually exclusive. The 52-bp mutation resulted in frameshift and premature termination (L367fsTer46). Klampfl et al. (2013) identified a total of 36 types of somatic insertion or deletion within exon 9 of CALR, all of which caused a frameshift to the same alternative reading frame and generated a novel C-terminal peptide in the mutant calreticulin. Klampfl et al. (2013) identified insertions or deletions in exon 9 of CALR in 88% of individuals with primary myelofibrosis with nonmutated JAK2 or MPL. The 52-bp deletion accounted for 53% of all cases of mutated CALR among several types of myeloproliferative neoplasm. Overexpression of this mutation resulted in cytokine-independent growth in vitro through the activation of STAT5 (601511). Nangalia et al. (2013) identified 23 patients with myelofibrosis who carried the L367fsTer46 mutation. Overall, Nangalia et al. (2013) identified 19 different somatic CALR mutations, all in exon 9 and all of which generated a +1 frameshift resulting in a mutant protein with a novel C terminal. CALR mutations were present in 18 of 32 patients (56%) with primary myelofibrosis and in 12 of 14 patients (86%) with progression of essential thrombocythemia to myelofibrosis. Neither Klampfl et al. (2013) nor Nangalia et al. (2013) detected CALR mutation in individuals with polycythemia vera. (less)
Pathogenic (Dec 19, 2013)	no assertion criteria provided Method: literature only	THROMBOCYTHEMIA, SOMATIC Affected status: not provided Allele origin: somatic	OMIM Accession: SCV000115336.2 First in ClinVar: Feb 11, 2014 Last updated: May 05, 2014	Publications: PubMed (2) PubMed: 24325356‚ 24325359 Comment on evidence: Klampfl et al. (2013) and Nangalia et al. (2013) identified a somatic 52-bp deletion in exon 9 of the CALR gene (1092_1143del) in patients with … (more) Klampfl et al. (2013) and Nangalia et al. (2013) identified a somatic 52-bp deletion in exon 9 of the CALR gene (1092_1143del) in patients with myeloproliferative neoplasms, including myelofibrosis (254450) and essential thrombocythemia (see 187950). CALR mutations and JAK2 and MPL mutations were mutually exclusive. The 52-bp mutation resulted in frameshift and premature termination (L367fsTer46). Klampfl et al. (2013) identified a total of 36 types of somatic insertion or deletion within exon 9 of CALR, all of which caused a frameshift to the same alternative reading frame and generated a novel C-terminal peptide in the mutant calreticulin. Klampfl et al. (2013) identified insertions or deletions in exon 9 of CALR in 88% of individuals with primary myelofibrosis with nonmutated JAK2 or MPL. The 52-bp deletion accounted for 53% of all cases of mutated CALR among several types of myeloproliferative neoplasm. Overexpression of this mutation resulted in cytokine-independent growth in vitro through the activation of STAT5 (601511). Nangalia et al. (2013) identified 23 patients with myelofibrosis who carried the L367fsTer46 mutation. Overall, Nangalia et al. (2013) identified 19 different somatic CALR mutations, all in exon 9 and all of which generated a +1 frameshift resulting in a mutant protein with a novel C terminal. CALR mutations were present in 18 of 32 patients (56%) with primary myelofibrosis and in 12 of 14 patients (86%) with progression of essential thrombocythemia to myelofibrosis. Neither Klampfl et al. (2013) nor Nangalia et al. (2013) detected CALR mutation in individuals with polycythemia vera. (less)

Comment:

While there are strong associations of this variant to thrombocythemia and myeloproliferative neoplasms, its oncogenicity and clinical impact in this case of acute myeloid leukemia is uncertain because the allele frequency decreased over time from 11% (progressive thrombocythemia) to 3% (AML in remission) to undetectable at AML relapse.

Comment:

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.	Nangalia J	The New England journal of medicine	2013	PMID: 24325359
Somatic mutations of calreticulin in myeloproliferative neoplasms.	Klampfl T	The New England journal of medicine	2013	PMID: 24325356

Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Essential thrombocythemia	Tier I (Strong) - diagnostic - supports diagnosis (1) Tier I (Strong) - prognostic - better outcome (1)		Jan 24, 2024	RCV003883131.2
Acute myeloid leukemia	Tier III Unknown (1)	Uncertain significance no assertion criteria provided	Jan 24, 2024	RCV003883130.1

Submissions - Somatic

Clinical impact Help The submitted somatic clinical impact 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)	Tumor type Help The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Tier I (Strong) - Diagnostic - supports diagnosis (Jan 24, 2024)	no assertion criteria provided Method: clinical testing	Essential thrombocythemia Affected status: unknown Allele origin: somatic	Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health Accession: SCV004697527.1 First In ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024	Publications: PubMed (2) PubMed: 24325359‚ 24325356 Comment: A large majority of myeloproliferative neoplasms with nonmutated JAK2 exhibit somatic CALR mutations. In a subset of such cases with essential thrombocythemia, 67% had CALR … (more) A large majority of myeloproliferative neoplasms with nonmutated JAK2 exhibit somatic CALR mutations. In a subset of such cases with essential thrombocythemia, 67% had CALR mutation. (less) Clinical Features: Bone marrow hypercellularity (present) Age: 70-79 years Sex: female Tissue: bone marrow with ET and 5-9% blasts Comment on evidence: A patient with a 10-year history of elevated and increasing platelet counts had a bone marrow biopsy in the absence of symptoms. The biopsy revealed … (more) A patient with a 10-year history of elevated and increasing platelet counts had a bone marrow biopsy in the absence of symptoms. The biopsy revealed thrombocythemia, with normal cytogenetics and without mutation of JAK2. CALR was not tested at that time. Approximately 2 ½ years later, a second BM biopsy was performed when the patient began having symptoms and counts were worsening. The biopsy had hypercellular marrow with 5-9% blasts and normal karyotype, but revealed this CALR exon 9 mutation at 11% allele frequency. She was started on 5-azyctadine; however, five months later, a BM biopsy showed 37% blasts positive for CD33, CD34, CD117, and HLA-DR, consistent with acute myeloid leukemia, and the karyotype included a novel translocation, t(4;7)(q12;q21.2), in 17 of 20 metaphase spreads examined. After induction chemotherapy with cytarabine and daunorubicin, a day-14 biopsy showed response to therapy, with a hypercellular marrow (80%) that displayed panmyelosis (trilineage hyperplasia), granulocytic hyperplasia, and megakaryocytic atypia without an increase in blasts, consistent with residual/persistent myeloid disease. A PB specimen revealed normocytic normochromatic anemia, leukocytosis, and thrombocytosis. Chromosome microarray analysis and NGS of DNA from a BM sample revealed no detectable genomic imbalances, the CALR deletion at 3.2% allele frequency, and no other pathogenic variants. After eight months in remission, the AML relapsed with blood DNA showing oncogenic somatic mutations at around 50% allele frequency, but no evidence of the CALR deletion. (less)
Tier I (Strong) - Prognostic - better outcome (Jan 24, 2024)	no assertion criteria provided Method: clinical testing	Essential thrombocythemia Affected status: unknown Allele origin: somatic	Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health Accession: SCV004697528.1 First In ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024	Publications: PubMed (1) PubMed: 24325356 Comment: In a cohort of 1107 myeloproliferative neoplasm patients, those with "mutated CALR had a lower risk of thromobsis and longer overall survival than patients with … (more) In a cohort of 1107 myeloproliferative neoplasm patients, those with "mutated CALR had a lower risk of thromobsis and longer overall survival than patients with mutated JAK2." (less) Clinical Features: Bone marrow hypercellularity (present) Age: 70-79 years Sex: female Tissue: bone marrow with ET and 5-9% blasts
Tier III Unknown (Jan 24, 2024)	no assertion criteria provided Method: clinical testing	Acute myeloid leukemia Affected status: unknown Allele origin: somatic	Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health Accession: SCV004697529.1 First In ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024	Comment: While there are strong associations of this variant to thrombocythemia and myeloproliferative neoplasms, its oncogenicity and clinical impact in this case of acute myeloid leukemia … (more) While there are strong associations of this variant to thrombocythemia and myeloproliferative neoplasms, its oncogenicity and clinical impact in this case of acute myeloid leukemia is uncertain because the allele frequency decreased over time from 11% (progressive thrombocythemia) to 3% (AML in remission) to undetectable at AML relapse. (less) Clinical Features: Bone marrow hypercellularity (present) , Granulocytic hyperplasia (present) Age: 70-79 years Sex: female Tissue: bone marrow with 37% blasts Method: Average 800x coverage of all exons from 275 cancer-related genes.

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Uncertain significance

(Jan 24, 2024)

Method: clinical testing

Acute myeloid leukemia

Affected status: unknown

Allele origin: somatic

Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health

Accession: SCV004697530.1
First In ClinVar: Mar 05, 2024
Last updated: Mar 05, 2024

Publications:: PubMed (1)
PubMed: 31562135

Comment:

While there are strong associations of this variant to thrombocythemia and myeloproliferative neoplasms, its oncogenicity and clinical impact in this case of acute myeloid leukemia … (more)

Clinical Features:

Bone marrow hypercellularity (present) , Granulocytic hyperplasia (present)

Age: 70-79 years

Sex: female

Tissue: bone marrow with 37% blasts

Method: Average 800x coverage of all exons from 275 cancer-related genes.

Comment:

A large majority of myeloproliferative neoplasms with nonmutated JAK2 exhibit somatic CALR mutations. In a subset of such cases with essential thrombocythemia, 67% had CALR mutation.

Comment:

In a cohort of 1107 myeloproliferative neoplasm patients, those with "mutated CALR had a lower risk of thromobsis and longer overall survival than patients with mutated JAK2."

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Mutant calreticulin in myeloproliferative neoplasms.	How J	Blood	2019	PMID: 31562135
Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.	Nangalia J	The New England journal of medicine	2013	PMID: 24325359
Somatic mutations of calreticulin in myeloproliferative neoplasms.	Klampfl T	The New England journal of medicine	2013	PMID: 24325356

Text-mined citations for rs1555760738 ...

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 Jun 23, 2024

ClinVar Genomic variation as it relates to human health

NM_004343.3(CALR):c.1092_1143del52 (p.Leu367Thrfs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs1555760738 ...