NM_005475.3(SH2B3):c.1183G>A (p.Glu395Lys) AND Thrombocythemia 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 10, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000760174.5

Allele description [Variation Report for NM_005475.3(SH2B3):c.1183G>A (p.Glu395Lys)]

NM_005475.3(SH2B3):c.1183G>A (p.Glu395Lys)

Gene:

SH2B3:SH2B adaptor protein 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.12

Genomic location:

Preferred name:

NM_005475.3(SH2B3):c.1183G>A (p.Glu395Lys)

HGVS:

NC_000012.12:g.111447491G>A
NG_011572.3:g.157186C>T
NG_021216.1:g.46544G>A
NM_001291424.1:c.577G>A
NM_005475.3:c.1183G>AMANE SELECT
NP_001278353.1:p.Glu193Lys
NP_005466.1:p.Glu395Lys
LRG_621t2:c.577G>A
LRG_621:g.46544G>A
LRG_621p2:p.Glu193Lys
LRG_864:g.157186C>T
NC_000012.11:g.111885295G>A
NM_005475.2:c.1183G>A

Protein change:

E193K

Links:

dbSNP: rs148636776

NCBI 1000 Genomes Browser:

rs148636776

Molecular consequence:

NM_001291424.1:c.577G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005475.3:c.1183G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Thrombocythemia 1 (THCYT1)
Synonyms:: Idiopathic thrombocythemia; THROMBOCYTOSIS 1; THROMBOCYTHEMIA, SOMATIC
Identifiers:: MONDO: MONDO:0008554; MedGen: C3277671; OMIM: 187950

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BE800884 (0)
MeSH
ARHGAP18 [Bos mutus]
ARHGAP18 [Bos mutus]
Gene ID:102283538

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000889996	Center for Precision Medicine, Vanderbilt University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 16, 2018)	germline	research, in vitro	PubMed (5) [See all records that cite these PMIDs] 25741868, 27651169, 15705783, 28484264, 29590070
SCV004176423	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004228500	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 10, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000889996

Center for Precision Medicine, Vanderbilt University Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 16, 2018)

germline

research, in vitro

PubMed (5)
[See all records that cite these PMIDs]

SCV004176423

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 1, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004228500

KCCC/NGS Laboratory, Kuwait Cancer Control Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 10, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	22	not provided	not provided	not provided	not provided	research, in vitro

Citations

PubMed

Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations.

Camps C, Petousi N, Bento C, Cario H, Copley RR, McMullin MF, van Wijk R, Ratcliffe PJ, Robbins PA, Taylor JC; WGS500 Consortium..

Haematologica. 2016 Nov;101(11):1306-1318. Epub 2016 Sep 20.

PubMed [citation]

PMID:: 27651169
PMCID:: PMC5394871

Lnk inhibits erythropoiesis and Epo-dependent JAK2 activation and downstream signaling pathways.

Tong W, Zhang J, Lodish HF.

Blood. 2005 Jun 15;105(12):4604-12. Epub 2005 Feb 10.

PubMed [citation]

PMID:: 15705783
PMCID:: PMC1894992

See all PubMed Citations (5)

Details of each submission

From Center for Precision Medicine, Vanderbilt University Medical Center, SCV000889996.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	22	not provided	not provided	research	PubMed (5)
2	not provided	not provided	not provided	not provided	in vitro	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	discovery		22	not provided	not provided	not provided
2	germline	unknown	not provided	not provided	discovery		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004176423.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004228500.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		1	not provided	not provided	clinical testing	PubMed (1)

Description

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 .

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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