SYNE1
protein-codingspectrin repeat containing nuclear envelope protein 1, the group of Spectrin repeat containing nuclear envelope family|KASH domain containing
Gene summary
This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]
- C6orf98
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~516.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0032778
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012549
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0012549
Submitter: ClinGen
Spectrin repeat-containing nuclear envelop protein 1 (*SYNE1*) was first reported in relation to autosomal recessive spinocerebellar ataxia 8 (SCAR8) in 2006 (Gros-Louis et al., PMID 17159980). The age of onset and phenotypic spectrum vary widely but can include adult onset pure ataxia, and a syndromic ataxia which can include but is not limited to, motor neuron dysfunction and scoliosis. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, spinocerebellar ataxia, autosomal recessive 8 (OMIM: 610743) and arthrogryposis multiplex congenita 3, myogenic type (OMIM: 618484). There are assertions in the literature of an autosomal dominant Emery-Dreifuss muscular dystrophy 4 (OMIM: 612998) associated with missense variation in *SYNE1* but will be curated seperately. 6 variants (3 nonsense, 1 frame-shift, and 2 canonical splice site) that have been reported in 6 probands in 2 publications (PMIDs 17159980, 27086870) are included in this curation. Genetic case evidence includes segregation from a family with a published LOD score of 3 for a 500 kb linkage region where *SYNE1* is the only gene. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by an animal model and expression study (PMIDs 19008300, 22768332). Expression in the brain is strong but there is also evidence of multple spliceforms with varying expression in other tissues. In a mouse model with the terminal KASH domain removed, mice homozygous for the change experienced high rates of death near birth from respiratory failure with surviving adults showed signs of abnormal gait, muscle pathology, kyphoscoliosis, hind limb weakness and cardiac conduction defects. In summary, there is definitive evidence supporting the relationship between *SYNE1* and autosomal recessive spinocerebellar ataxia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebellar Ataixa GCEP on the meeting date December 10, 2025 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0013071
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0012549
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013071
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012549
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0012549
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013071
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012549
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013071
Submitter: Illumina
Inheritance Pattern: AR
Disease ID:MONDO:0012549
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0032778
Submitter: ClinGen
Spectrin repeat-containing nuclear envelope protein 1 (*SYNE1*:protein name nesprin) was first reported in relation to autosomal recessive arthrogryposis multiplex congenita in 2009 (Attali et al., PMID: 19542096). Features of *SYNE1*-related arthrogryposis can include but are not limited to: decreased fetal movement, congenital contractures, hypotonia, kyphoscoliosis and or respiratory difficulty. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found a difference in the molecular mechanism and phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, spinocerebellar ataxia, autosomal recessive 8 (OMIM: 610743) and arthrogryposis multiplex congenita 3, myogenic type (OMIM: 618484). This split is based on the observation that the arthrogryposis entity is entirely associated with biallelic loss of function variants that would affect the nesprin-1-alpha isoform. The split curation for autosomal recessive *SYNE1*-related spinocerebellar ataxia has been curated separately. 5 variants (3 nonsense and 2 truncating) that have been reported in 5 probands in 5 publications (PMIDs: 19542096, 24319099, 27782104, 35739559, 30626539) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by a mouse model and an expression study showing expresion of the nesprin-1-alpha isoform is nearly entirely unique to skeletal muscle and cardiac tissue (PMIDs: 19008300, 24718612). No cerebellar features have been noted in the probands in the literature to date however the variants in this curation would also lead to loss of function in the large nesprin isoform which has been associated with the *SYNE1*-related spinocerebellar ataxia entity. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date December 10, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0017892
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0020336
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0032778
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: One reported patient was found to have left ventricular basal and septal hypertrophy with mild diastolic dysfunction, and surveillance (eg, with echocardiogram) may allow early medical management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SYNE1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_182961.4. 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 | 144 | 1363 | 17 | 1524 | ||
| missense | 3 | 9 | 3261 | 184 | 33 | 3490 |
| nonsense | 111 | 66 | 5 | 182 | ||
| start loss | 1 | 1 | ||||
| frameshift | 83 | 61 | 7 | 151 | ||
| splice donor/acceptor (+/-2bp) | 14 | 53 | 19 | 1 | 87 | |
| Total | 211 | 189 | 3437 | 1548 | 50 | 5435 |
Highest pathogenic variant AF is 0.00012490139
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_892006.3 | 144 | MANE Select | |
| Ensembl | ENSP00000356224.5 | 144 | MANE Select | |
| RefSeq | NP_001334630.1 | 17 | Standard | |
| RefSeq | NP_001334631.1 | 18 | MANE Plus Clinical |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| syne1b | Danio rerio | Structure: post-vent region Quality: increased curvature abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- miR-targeted genes in epithelium - TarBase
- miR-targeted genes in lymphocytes - TarBase
- miR-targeted genes in muscle cell - TarBase
Biological Process
- nucleus organization
- Golgi organization
- spermatogenesis
- muscle cell differentiation
- cytoskeletal anchoring at nuclear membrane
Molecular Function
- RNA binding
- actin binding
- protein binding
- lamin binding
- enzyme binding
Cellular Component
- P-body
- nucleus
- nuclear envelope
- nuclear outer membrane
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367255
- Coding exons
- 144
- Length
- 516118
- Individuals with no LoFs
- 125312
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 436
- Defined
- 125748
- p
- 0.00174
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.291 | 4465 | 4.41e+3 | 1.01 | 0.000252 | 58271 |
| Missense (PolyPhen) | 1067 | 1162.1 | 0.91819 | 16036 | ||
| Synonymous | -1.64 | 1798 | 1.71e+3 | 1.05 | 0.000101 | 16092 |
| Loss of Function | 12.8 | 182 | 487 | 0.374 | 0.0000264 | 5737 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0018 | 0.0018 | notable |
| Latino/Admixed American | 0.0020 | 0.0020 | notable |
| Ashkenazi Jewish | 0.00062 | 0.00060 | rare |
| East Asian | 0.0015 | 0.0015 | notable |
| Finnish | 0.0012 | 0.0012 | notable |
| European (Non-Finnish) | 0.0019 | 0.0019 | notable |
| South Asian | 0.0017 | 0.0017 | notable |
| Other | 0.0018 | 0.0018 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization. As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. May be involved in nucleus-centrosome attachment and nuclear migration in neural progenitors implicating LINC complex association with SUN1/2 and probably association with cytoplasmic dynein-dynactin motor complexes; SYNE1 and SYNE2 may act redundantly. Required for centrosome migration to the apical cell surface during early ciliogenesis. May be involved in nuclear remodeling during sperm head formation in spermatogenenis; a probable SUN3:SYNE1/KASH1 LINC complex may tether spermatid nuclei to posterior cytoskeletal structures such as the manchette. {ECO:0000250|UniProtKB:Q6ZWR6, ECO:0000269|PubMed:11792814, ECO:0000269|PubMed:18396275}.;
- Disease
- DISEASE: Spinocerebellar ataxia, autosomal recessive, 8 (SCAR8) [MIM:610743]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR8 is an autosomal recessive form. {ECO:0000269|PubMed:17159980}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Emery-Dreifuss muscular dystrophy 4, autosomal dominant (EDMD4) [MIM:612998]: A form of Emery-Dreifuss muscular dystrophy, a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system, early contractures of the elbows, Achilles tendons and spine, and cardiomyopathy associated with cardiac conduction defects. {ECO:0000269|PubMed:17761684}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.461
Intolerance Scores
- LoFtool
- 0.881
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.65
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.669
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |