Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001035277 | SCV001198600 | pathogenic | Charcot-Marie-Tooth disease type 4 | 2023-08-08 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 4 of the SH3TC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SH3TC2 are known to be pathogenic (PMID: 20220177, 27068304). This variant is present in population databases (rs145670786, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with hereditary neuropathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 694977). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Gene |
RCV001556920 | SCV001778588 | likely pathogenic | not provided | 2019-07-29 | criteria provided, single submitter | clinical testing | Observed in a large cohort of patients with CMT; however, no other information was provided (DiVincenzo et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Canonical splice site variant predicted to destroy the canonical splice acceptor site in intron 4 and expected to cause abnormal gene splicing; This variant is associated with the following publications: (PMID: 31827005, 25614874) |
| Ambry Genetics | RCV002352497 | SCV002619989 | likely pathogenic | Inborn genetic diseases | 2020-10-26 | criteria provided, single submitter | clinical testing | The c.386-2A>C intronic variant results from an A to C substitution two nucleotides upstream from coding exon 5 in the SH3TC2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the missing amino acids is unknown. This alteration has been reported in trans with other pathogenic alterations in SH3TC2 in individuals with clinical features consistent with Charcot-Marie-Tooth disease, type 4C (CMT4C) (Cortese A et al. Neurology, 2020 01;94:e51-e61). Based on data from gnomAD, the C allele has an overall frequency of 0.001% (3/251434) total alleles studied. The highest observed frequency was 0.003% (3/113740) of European (non-Finnish) alleles. This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Genesis Genome Database | RCV000857159 | SCV000999740 | uncertain significance | Distal spinal muscular atrophy | 2019-08-14 | no assertion criteria provided | research |