• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
SH2D1A (HGNC:10820) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
SH2 domain containing 1A
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
IMD5, LYP
Alias symbols
XLP, MTCP1, DSHP, XLPD, EBVS, SAP
%HI
11.82(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.39(Read more about gnomAD pLI score)
LOEUF
0.96(Read more about gnomAD LOEUF score)
Cytoband
Xq25
Genomic Coordinates
GRCh37/hg19: chrX:123480413-123507010 NCBI Ensembl UCSC
GRCh38/hg38: chrX:124346563-124373160 NCBI Ensembl UCSC
MANE Select Transcript
NM_002351.5 ENST00000371139.9 (Read more about MANE Select)
Function
Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244, LY9, CD84, SLAMF6 and SLAMF7. In SLAM signaling seems to cooperate with SH2D1B/EAT-2. Initially it has been proposed that association with SLAMF1 prevents SLAMF1 binding to inhibitory effectors including INPP5D/SHIP1 and PTPN11/SHP-2 (PubMed:11806999). However, by simultaneous interactions, recruits FYN which subsequently phosphorylates and activates SLAMF1 (PubMed:12458... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-2171
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
01/27/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • X-linked lymphoproliferative disease due to SH2D1A deficiency Monarch
HI Evidence:
  • PUBMED: 11049992
    Sumegi et al (2000) reported that analysis of 35 families from the X-linked lymphoproliferative disease (XLP) Registry revealed 28 different mutations in 34 families, including large genomic deletions (n = 3), small intragenic deletions (n = 10), splice-site (n = 3), nonsense (n = 3), and missense (n = 9) mutations.
  • PUBMED: 11159547
    Arico et al (2001) analyzed 25 patients diagnosed with HPLH for germline mutations in the SH2D1A gene. They identified 4 patients with XLP and carried a mutation in the SH2D1A gene. Two had hemizygous deletions encompassing SH2D1A exon 1 and 2 had nonsense mutations.
  • PUBMED: 31144249
    Nademi et al (2019) repotted three siblings from a non-consanguineous family of Yemeni origin with hemizygous deletions of exon 2 of the SH2D1A gene. All three patient were diagnosed with XLP but manifested different phenotypes at different ages.
HI Evidence Comments:
X-linked lymphoproliferative syndrome (XLP), or Duncan disease, is a primary immunodeficiency characterized by severe immune dysregulation often after viral infection, typically with Epstein-Barr virus (EBV), predominantly presented with hemophagocytic lymphohistiocytosis (HLH), dysgammaglobulinemia and lymphoproliferative disease. Loss of function mutations in SH2D1A cause XLP. More than 113 SH2D1A pathogenic variants have been identified to contribute to XLP-associated phenotype: ~25% are splicing defects or frameshift variants and ~25% are large deletion of one or more exons or the entire gene (HGMD, PMID: 32461654; GeneReviews). Multiple functional studies (PMID: 11404475; 15774582;18843362) including SH2D1A knock out mice model further demonstrated the association between SH2D1A deficiency and XLP-related phenotype. PMID: 15774582 Morra et al (2005) found that mice lacking Sh2d1a had severely impaired primary and secondary responses of all Ig subclasses to specific antigens, even in the absence of viral infection. both defective T and B cells exist in the absence of SH2D1A mice model, which may explain the progressive dysgammaglobulinemia in a subset of X-linked lympho-proliferative disease patients.
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
Focal duplication of SH2D1A is not identified.
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)