The missense c.1183G>A(p.Glu395Lys) variant in SH2B3 gene has been reported in heterozygous state in individuals affected with Thrombocythemia (Bastarache L, et. al., 2018). The variant is reported with an allele frequency of 0.01% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Glu395Lys in SH2B3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 395 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_005475.3(SH2B3):c.1183G>A (p.Glu395Lys)
Germline
Classification
Help
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.
(4)
Help
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/Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005475.3(SH2B3):c.1183G>A (p.Glu395Lys)
Variation ID: 619973 Accession: VCV000619973.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q24.12 12: 111447491 (GRCh38) [ NCBI UCSC ] 12: 111885295 (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 19, 2019 Jan 26, 2024 Jan 10, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005475.3:c.1183G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005466.1:p.Glu395Lys missense NM_001291424.1:c.577G>A NP_001278353.1:p.Glu193Lys missense NM_005475.2:c.1183G>A NC_000012.12:g.111447491G>A NC_000012.11:g.111885295G>A NG_011572.3:g.157186C>T NG_021216.1:g.46544G>A LRG_621:g.46544G>A LRG_621t2:c.577G>A LRG_621p2:p.Glu193Lys LRG_864:g.157186C>T - Protein change
- E193K, E395K
- Other names
- -
- Canonical SPDI
- NC_000012.12:111447490:G:A
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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.
-
Exome Aggregation Consortium (ExAC) 0.00013
The Genome Aggregation Database (gnomAD), exomes 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00022
The Genome Aggregation Database (gnomAD) 0.00025
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| SH2B3 | - | - |
GRCh38 GRCh37 |
102 | 111 | |
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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 16, 2018 | RCV000760171.2 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 10, 2024 | RCV000760174.5 |
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
(Mar 16, 2018)
|
criteria provided, single submitter
Method: research, in vitro
|
Primary familial polycythemia due to EPO receptor mutation
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Center for Precision Medicine, Vanderbilt University Medical Center
Accession: SCV000889990.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
Observation 1:
Number of individuals with the variant: 22
Clinical Features:
malaise and fatigue (present) , abdominal pain (present) , hypertension (present) , pain in joint (present) , other headache syndromes (present) , migraine (present) , … (more)
malaise and fatigue (present) , abdominal pain (present) , hypertension (present) , pain in joint (present) , other headache syndromes (present) , migraine (present) , phlebitis and thrombophlebitis (present) , peripheral or central vertigo (present) , pruritus (present) , splenomegaly (present) , myocardial infarction (present) , fluid overload (present) , respiratory failure/insufficiency/arrest (present) , coagulation defects (present) , cerebral ischemia (present) , other dyspnea (present) (less)
Method: A phenotype risk score (PheRS) for Familial erythrocytosis 1 was calculated by mapping the disease HPO terms to phecodes, clustered ICD-9 codes that represent phenotypes in the electronic health records. When applied to 21,701 European individuals, the PheRS for this disease showed significant association with the rs148636776 variant. Some individuals that are heterozygous for this variant carry phecodes that are consistent with phenotypes associated with this disease. Additionally, a biological assay found that this variant alters the function of this gene product in vitro.
Observation 2:
Method: Plasmids expressing wild type or rs148636776 constructs were transiently transfected in HEK293T cells with JAK2 and EPOR. The cells were stimulated by Erythropoietin and lysates were collected for Western blot analysis of pERK. Expression of wild type SH2B3 results in attenuation of pERK signal compared to vector only controls. Expression of the rs148636776 variant is unable to attenuate pERK signal.
Result:
SH2B3 directly interacts with JAK2 to attenuate activation of cytokine signaling in hemapoietic cells. This process can be monitored in vitro, by stimulating HEK293T cells with Erythropoietin (EPO), which increases pERK levels. Transient transfection of wild type SH2B3 in HEK293T cells, suppresses the EPO stimulation effects, by attenuating JAK2 activity. Transient transfection of the rs148636776 variant does not suppress EPO stimulation (pERK levels remain high). A previously identified SH2B3 mutation, R392E, is also unable to quench EPO stimulation in vitro. These results support the prediction that the rs148636776 variant affects the function of the SH2B3 gene product (n=4 independent experiments, p<0.003 unpaired two-tail t test)
|
|
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Pathogenic
(Mar 16, 2018)
|
criteria provided, single submitter
Method: research, in vitro
|
Thrombocythemia 1
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Center for Precision Medicine, Vanderbilt University Medical Center
Accession: SCV000889996.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
Observation 1:
Number of individuals with the variant: 22
Clinical Features:
hypertension (present) , myeloproliferative disease (present) , diseases of blood and blood forming organs (present) , peripheral vascular diseases (present) , splenomegaly (present)
Method: A phenotype risk score (PheRS) for Essential thrombocythemia was calculated by mapping the disease HPO terms to phecodes, clustered ICD-9 codes that represent phenotypes in the electronic health records. When applied to 21,701 European individuals, the PheRS for this disease showed significant association with the rs148636776 variant. Some individuals that are heterozygous for this variant have phecodes that are consistent with phenotypes associated with this disease. Additionally, a biological assay found that this variant alters the function of this gene product in vitro.
Observation 2:
Method: Plasmids expressing wild type or rs148636776 constructs were transiently transfected in HEK293T cells with JAK2 and EPOR. The cells were stimulated by Erythropoietin and lysates were collected for Western blot analysis of pERK. Expression of wild type SH2B3 results in attenuation of pERK signal compared to vector only controls. Expression of the rs148636776 variant is unable to attenuate pERK signal.
Result:
SH2B3 directly interacts with JAK2 to attenuate activation of cytokine signaling in hemapoietic cells. This process can be monitored in vitro, by stimulating HEK293T cells with Erythropoietin (EPO), which increases pERK levels. Transient transfection of wild type SH2B3 in HEK293T cells, suppresses the EPO stimulation effects, by attenuating JAK2 activity. Transient transfection of the rs148636776 variant does not suppress EPO stimulation (pERK levels remain high). A previously identified SH2B3 mutation, R392E, is also unable to quench EPO stimulation in vitro. These results support the prediction that the rs148636776 variant affects the function of the SH2B3 gene product (n=4 independent experiments, p<0.003 unpaired two-tail t test)
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Likely pathogenic
(Mar 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Thrombocythemia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004176423.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The missense c.1183G>A(p.Glu395Lys) variant in SH2B3 gene has been reported in heterozygous state in individuals affected with Thrombocythemia (Bastarache L, et. al., 2018). The variant … (more)
The missense c.1183G>A(p.Glu395Lys) variant in SH2B3 gene has been reported in heterozygous state in individuals affected with Thrombocythemia (Bastarache L, et. al., 2018). The variant is reported with an allele frequency of 0.01% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Glu395Lys in SH2B3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 395 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Abnormality of blood and blood-forming tissues (present)
|
|
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Pathogenic
(Jan 10, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Thrombocythemia 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004228500.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
SH2B3 is an adaptor protein that regulates growth factor and cytokine signaling. Mutations are found in hematopoietic disorders including leukemias and myeloid disease. This mutation … (more)
SH2B3 is an adaptor protein that regulates growth factor and cytokine signaling. Mutations are found in hematopoietic disorders including leukemias and myeloid disease. This mutation reported in ClinVar(619973 ) associated with Autosomal dominant Thrombocythemia 1 . (less)
Age: 40-49 years
Sex: female
|
Comment:
Comment:
SH2B3 is an adaptor protein that regulates growth factor and cytokine signaling. Mutations are found in hematopoietic disorders including leukemias and myeloid disease. This mutation reported in ClinVar(619973 ) associated with Autosomal dominant Thrombocythemia 1 .
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:
The missense c.1183G>A(p.Glu395Lys) variant in SH2B3 gene has been reported in heterozygous state in individuals affected with Thrombocythemia (Bastarache L, et. al., 2018). The variant is reported with an allele frequency of 0.01% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid change p.Glu395Lys in SH2B3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 395 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.
Comment:
SH2B3 is an adaptor protein that regulates growth factor and cytokine signaling. Mutations are found in hematopoietic disorders including leukemias and myeloid disease. This mutation reported in ClinVar(619973 ) associated with Autosomal dominant Thrombocythemia 1 .
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phenotype risk scores identify patients with unrecognized Mendelian disease patterns. | Bastarache L | Science (New York, N.Y.) | 2018 | PMID: 29590070 |
| The role of LNK/SH2B3 genetic alterations in myeloproliferative neoplasms and other hematological disorders. | Maslah N | Leukemia | 2017 | PMID: 28484264 |
| Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations. | Camps C | Haematologica | 2016 | PMID: 27651169 |
| Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways. | Tong W | Blood | 2005 | PMID: 15705783 |
Text-mined citations for rs148636776 ...
HelpThese 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 Oct 08, 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.