Hereditary Neuropathy_CMT - isolated
Gene: SH3TC2
AR form of CMT is particularly severe and disabling from infancy. CMT4C is an early-onset demyelinating form characterized by a severe scoliosis and is due to mutations in the SH3TC2 gene (PMID: 19744956).
Lupski et al 2010 describes 1 family with CMT4C where there are family members carrying heterozygous mutations in SH3TC2 with dominant mild mononeuropathy of the median nerve. The authors postulated a gain of function mechanism for a specific Y169H variant but no functional studies were provided (OMIM). There weren’t any other reports suggesting this mechanism in the literature. This is the only report for AD disease - LIMITED evidence.
LOF evidence: COS-7 cells transfected with missense mutant plasmids demonstrated loss or reduction in localisation to plasma membrane WT plasmid, however, this only applied to missense variants clustered around the first TPR domain (PMID: 19744956). Roberts et al (2010) showed that SH3TC2 constructs harbouring missense and nonsense CMT4C-associated pathogenic mutations failed to localize to the recycling endosome, failed to associate with Rab11 and had no effects on transferring receptor dynamics when over expressed compared to WT constructs when expressed in HeLa cells (PMID: 20028792).Created: 9 Oct 2020, 8:25 a.m. | Last Modified: 9 Oct 2020, 8:25 a.m.
Panel Version: 0.55
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Charcot-Marie-Tooth disease, type 4C MIM#601596, Mononeuropathy of the median nerve, mild MIM#613353
Publications
AR form of CMT is particularly severe and disabling from infancy. CMT4C is an early-onset demyelinating form characterized by a severe scoliosis and is due to mutations in the SH3TC2 gene (PMID: 19744956).
Lupski et al 2010 describes 1 family with CMT4C where there are family members carrying heterozygous mutations in SH3TC2 with dominant mild mononeuropathy of the median nerve. The authors postulated a gain of function mechanism for a specific Y169H variant but no functional studies were provided (OMIM). There weren’t any other reports suggesting this mechanism in the literature. This is the only report for AD disease - questionable relationship
LOF evidence:
COS-7 cells transfected with missense mutant plasmids demonstrated loss or reduction in localisation to plasma membrane WT plasmid, however, this only applied to missense variants clustered around the first TPR domain (PMID: 19744956). Roberts et al (2010) showed that SH3TC2 constructs harbouring missense and nonsense CMT4C-associated pathogenic mutations failed to localize to the recycling endosome, failed to associate with Rab11 and had no effects on transferring receptor dynamics when over expressed compared to WT constructs when expressed in HeLa cells (PMID: 20028792).Created: 9 Oct 2020, 4:32 a.m. | Last Modified: 9 Oct 2020, 4:32 a.m.
Panel Version: 0.4843
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Charcot-Marie-Tooth disease, type 4C MIM#601596, Mononeuropathy of the median nerve, mild MIM#613353
Publications
Gene: sh3tc2 has been classified as Green List (High Evidence).
Publications for gene: SH3TC2 were set to
Mode of inheritance for gene: SH3TC2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
gene: SH3TC2 was added gene: SH3TC2 was added to Hereditary Neuropathy - isolated_RMH. Sources: Royal Melbourne Hospital,Expert Review Green Mode of inheritance for gene: SH3TC2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: SH3TC2 were set to HMSN; Charcot Marie Tooth disease, type 4C, 601596; Mononeuropathy of the median nerve, mild, 613353