SH2D1A

protein-coding

SH2 domain containing 1A, the group of SH2 domain containing

Gene summary

This gene encodes a protein that plays a major role in the bidirectional stimulation of T and B cells. This protein contains an SH2 domain and a short tail. It associates with the signaling lymphocyte-activation molecule, thereby acting as an inhibitor of this transmembrane protein by blocking the recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to its docking site. This protein can also bind to other related surface molecules that are expressed on activated T, B and NK cells, thereby modifying signal transduction pathways in these cells. Mutations in this gene cause lymphoproliferative syndrome X-linked type 1 or Duncan disease, a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus, with symptoms including severe mononucleosis and malignant lymphoma. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

IMD5
LYP

MANE transcript

NM_002351.5

Inheritance

ClinVar variants

P:43U:58B:28

Top phenotype

Lymphoproliferative syndrome, X-linked, 1

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chrX:124,227,868-124,373,197

External References & Databases

Ensembl (ENSG00000183918)

Transcript & Mutation Effects

hg38 • Region Span ~145.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked lymphoproliferative disease due to SH2D1A deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0024551

Submitter: G2P

X-linked lymphoproliferative disease due to SH2D1A deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0024551

Submitter: Labcorp Genetics (formerly Invitae)

X-linked lymphoproliferative disease due to SH2D1A deficiencyDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0024551

Submitter: ClinGen

*SH2D1A* was reported as the gene associated with X-linked lymphoproliferative syndrome in 1998 simultaneously by three different groups (PMID 9811875, 9771704, 9774102). First described clinically in 1975 (PMID 48119), X-linked lymphoproliferative disease due to *SH2D1A* deficiency (known as XLP1) is characterised as one of fulminant infectious mononucleosis, lymphoproliferative disorders or dysgammaglobulinaemia, generally developing after first exposure to EBV. Patients may have other autoimmune features such as aplastic anaemia, vasculitis and colitis. Since the discovery of the *SH2D1A* gene, many genetic variants spanning the length of the gene have been described in affected patients, including large deletions, splice-site mutations, nonsense and missense mutations (see PMID 11049992 for a description of 35 families with at least two affected individuals in each family). The mechanism is known to be loss of function. Included in this curation are 6 variants reaching the maximum scorable genetic evidence (PMID 11049992, PMID 9811875, PMID 9774102, PMID11159547, PMID 23829589, PMID 20632414). This gene-disease association is supported by experimental evidence, including animal models, expression studies and gene transfer rescue studies (PMID 12966553, 9774102, 29705247). *SH2D1A *encodes of SAP, a protein basally expressed in NK and T cells (PMID 9774102), and interacts with SLAM and other members of the CD2 subfamily of cellular receptors (PMID 15661030 for summary). Deletion of exon 2 of the sap gene in mice recapitulates the phenotype seen in humans with absence of SAP protein, susceptibility to murine gammaherpesvirus-68 and dysgammaglobulinaemia (PMID 12966553). Transduction of wildtype *SH2D1A* in patient T-cells with a lentiviral vector restores SAP expression and rescues defective T-follicular helper cell function and cytotoxicity (PMID 29705247). HSCT is a curative option in patients with XLP1, and lentiviral gene therapy has shown promising results in both murine models and patient cells (PMID 30459818, PMID 39309261, PMID 23223356). Taken together, the association between *SH2D1A* and X-linked lymphoproliferative disease due to *SH2D1A* deficiency is definitive.

X-linked lymphoproliferative disease due to SH2D1A deficiencySTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0024551

Submitter: PanelApp Australia

X-linked lymphoproliferative disease due to SH2D1A deficiencySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0024551

Submitter: Orphanet

Clinical Genomic Database (CGD)

Lymphoproliferative syndrome, X-linked, 1XL

Manifestation: Allergy/Immunology/Infectious; Hematologic; Oncologic

Intervention: Allergy/Immunology/Infectious; Hematologic; Oncologic

Rationale: Surveillance for EBV infections is indicated; Prompt recognition and treatment of hemophagocytic lymphohistiocytosis (with immunologic agents or rituximab in the case of EBV infection); Treatment for individuals with hypogammaglobulinemia (with IVIG) may be beneficial; Awareness of the increased risk of lymphoma may allow prompt recognition and treatment; HSCT has been described, and is indicated in many individuals

Refs: 4852784; 48119; 7188959; 6283885; 1847089; 8559596; 9771704; 11133747; 17620557; 20926771; 21971331; 32374962

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SH2D1A variants in ClinVar

11 Conditions Cataloged

X-linked lymphoproliferative disease due to SH2D1A deficiencyTotal: 112

not providedTotal: 28

SH2D1A-related disorderTotal: 10

Inborn genetic diseasesTotal: 8

not specifiedTotal: 7

Autoinflammatory syndromeTotal: 5

Lymphoproliferative syndrome with absent SAP expressionTotal: 4

X-linked lymphoproliferative syndromeTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002351.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	6 clinvar	23 clinvar	2 clinvar	32
missense	6 clinvar	7 clinvar	47 clinvar	3 clinvar		63
nonsense	7 clinvar	1 clinvar				8
start loss	2 clinvar	1 clinvar				3
frameshift	5 clinvar	1 clinvar				6
splice donor/acceptor (+/-2bp)	8 clinvar	4 clinvar	5 clinvar			17
Total	28	15	58	26	2	129

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002351.5	RefSeq	NP_002342.1	4	MANE Select
ENST00000371139.9	Ensembl	ENSP00000360181.5	4	MANE Select
NM_001114937.3	RefSeq	NP_001108409.1	4	Standard
ENST00000360027.5	Ensembl	ENSP00000353126.4	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Natural killer cell mediated cytotoxicity - Homo sapiens (human)
Measles - Homo sapiens (human)
Integrated Lung Cancer Pathway
Immune System
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

Biological Process

adaptive immune response
humoral immune response
cellular defense response
cell-cell signaling
positive regulation of signal transduction

Molecular Function

SH3/SH2 adaptor activity
protein binding

Cellular Component

cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371139
Coding exons: 4
Length: 26812
Individuals with no LoFs: 125214
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125215
p: 0.00000399

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.69	17	50.9	0.334	0.00000395	816
Missense (PolyPhen)		6	25.673	0.23371		391
Synonymous	0.260	19	20.5	0.927	0.00000178	253
Loss of Function	1.64	1	4.93	0.203	3.84e-7	84

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000036	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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:12458214). Positively regulates CD244/2B4- and CD84- mediated natural killer (NK) cell functions. Can also promote CD48-, SLAMF6 -, LY9-, and SLAMF7-mediated NK cell activation. In the context of NK cell-mediated cytotoxicity enhances conjugate formation with target cells (By similarity). May also regulate the activity of the neurotrophin receptors NTRK1, NTRK2 and NTRK3. {ECO:0000250|UniProtKB:O88890, ECO:0000269|PubMed:11806999, ECO:0000269|PubMed:12458214, ECO:0000305|PubMed:21219180}.;

Recessive Scores

pRec: 0.453

Intolerance Scores

LoFtool: 0.413
RVIS EVS: 0.06
RVIS percentile EVS: 58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Low	Low	Low
Cancer	Low	Low	Low