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SH3TC2
SH3 domain and tetratricopeptide repeats 2
SH3TC2 is located on the long (q) arm of chromosome 5, at band 5q32. Arm ratio per GRCh38 - banding schematic.
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Overview
SH3TC2 (SH3 domain and tetratricopeptide repeats 2) is located on chromosome 5q32 and encodes a 1,288 amino acid protein involved in peripheral nerve maintenance. The gene plays an essential role in supporting Schwann cells, which form the insulating myelin sheath around nerve fibres. Pathogenic variants in SH3TC2 are a common cause of autosomal recessive Charcot-Marie-Tooth disease type 4C, characterising a significant proportion of inherited peripheral neuropathy cases worldwide. The gene is included in UK NHS hereditary neuropathy panels, reflecting its clinical importance for diagnosing progressive nerve disorders.
What the gene does
The SH3TC2 protein functions as a scaffolding molecule within Schwann cells, the specialised cells responsible for myelinating peripheral nerves. Through its multiple protein-interaction domains, SH3TC2 coordinates cellular processes required for myelin formation and maintenance. The protein localises to the endosomal recycling compartment, where it regulates membrane trafficking and the distribution of proteins essential for myelination. Research suggests SH3TC2 influences how Schwann cells sort and recycle membrane components during myelin synthesis. Disruption of this trafficking system appears to compromise the structural integrity of the myelin sheath, leading to progressive nerve dysfunction. The protein's role in endosomal dynamics positions it as a critical regulator of peripheral nerve health, particularly during periods of myelin turnover and repair.
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Chromosome location
SH3TC2 is positioned at chromosomal band 5q32 on the long arm of chromosome 5. The gene spans a substantial genomic region and contains multiple exons encoding the full-length protein. This chromosomal location has been associated with linkage signals in families affected by autosomal recessive neuropathy.
Protein structure
The SH3TC2 protein comprises 1,288 amino acids organised into distinct functional modules. Two SH3 domains (SH3 1 spanning amino acids 176-240 and SH3 2 spanning amino acids 268-331) mediate protein-protein interactions, enabling SH3TC2 to bind cellular partners involved in membrane trafficking. The protein contains eight tetratricopeptide repeat (TPR) motifs distributed across its C-terminal region: TPR 1 (amino acids 528-561), TPR 2 (amino acids 757-790), TPR 3 (amino acids 836-869), TPR 4 (amino acids 1001-1037), TPR 5 (amino acids 1084-1118), TPR 6 (amino acids 1119-1152), TPR 7 (amino acids 1166-1199), and TPR 8 (amino acids 1210-1244). These TPR repeats typically facilitate protein assembly and scaffolding functions. Two disordered regions (amino acids 386-405 and 410-444) likely provide structural flexibility between ordered domains.
Key variants
Pathogenic variants in SH3TC2 most commonly result in loss of protein function through nonsense mutations, frameshift insertions or deletions, and splice-site alterations. Missense variants affecting conserved residues within the SH3 or TPR domains can also disrupt protein stability or interaction capacity. Certain populations exhibit founder mutations at elevated frequencies, contributing to higher carrier rates in specific ethnic groups.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1679del | p.Gly560fs | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.2211C>A | p.Cys737Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.2551_2554dup | p.Val852fs | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease |
c.3627T>A | p.Tyr1209Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4C |
c.383T>G | p.Leu128Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4C |
c.620C>G | p.Ser207Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.798T>G | p.Tyr266Ter | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.819dup | p.Lys274Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease type 4 |
c.822_850dup | p.Lys284delinsArgProTer | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease |
c.929dup | p.Ser312fs | Pathogenic/Likely pathogenic | ★★☆☆ | Susceptibility to mononeuropathy of the median nerve, mild |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in SH3TC2 cause Charcot-Marie-Tooth disease type 4C, an autosomal recessive form of inherited peripheral neuropathy. Affected individuals typically present with progressive weakness and sensory loss in the feet and hands, often beginning in childhood or adolescence. Early spinal curvature and foot deformities are common features. The condition shows variable severity, with some individuals experiencing milder symptoms whilst others develop substantial mobility impairment. SH3TC2-related neuropathy represents one of the more frequent genetic causes of autosomal recessive Charcot-Marie-Tooth disease in certain regions.
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UK clinical status
SH3TC2 is listed on NHS Genomic Medicine Service panels for hereditary neuropathy and hereditary neuropathy or pain disorder, both with green classification status. This inclusion reflects the gene's established role in diagnosing inherited peripheral nerve disorders within the NHS diagnostic pathway. Testing for SH3TC2 variants may be offered when clinical features suggest hereditary neuropathy, particularly in consanguineous families or populations with elevated carrier frequencies.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What conditions are associated with SH3TC2 variants?
Pathogenic variants in SH3TC2 cause autosomal recessive Charcot-Marie-Tooth disease type 4C, characterised by progressive peripheral nerve dysfunction. Affected individuals typically develop muscle weakness, sensory loss, and skeletal abnormalities beginning in childhood or adolescence.
How is SH3TC2-related neuropathy inherited?
SH3TC2-related Charcot-Marie-Tooth disease follows an autosomal recessive inheritance pattern. An individual must inherit pathogenic variants from both parents to develop the condition, whilst carriers with one variant typically remain unaffected.
Is SH3TC2 tested on the NHS?
Yes, SH3TC2 is included on NHS Genomic Medicine Service panels for hereditary neuropathy. Testing may be offered when clinical features suggest inherited peripheral nerve disease, particularly in families with consanguinity or relevant ancestry.