Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001053102 | SCV001217344 | uncertain significance | Microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome | 2019-12-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glutamine at codon 445 of the SPATA5 protein (p.Arg445Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant also falls at the last nucleotide of exon 7 of the SPATA5 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs372616063, ExAC 0.002%). This variant has not been reported in the literature in individuals with SPATA5-related conditions. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |