Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000637290 | SCV000758738 | likely pathogenic | Congenital myopathy 4B, autosomal recessive; Congenital myopathy with fiber type disproportion | 2020-11-26 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different missense substitution at this codon (p.Leu100Met) has been reported in the literature in a family affected with congenital fiber type disproportion, however, the clinical significance of this variant is unknown (PMID: 22749829, 18300303, 26307083). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported in individuals affected with congenital fibre-type disproportion (PMID: 24692096). It has also been shown to segregate with suspected nemaline myopathy in a family (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 100 of the TPM3 protein (p.Leu100Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. |