Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000796039 | SCV000935530 | uncertain significance | Hereditary sensory neuropathy-deafness-dementia syndrome | 2018-12-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with glycine at codon 151 of the DNMT1 protein (p.Arg151Gly). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and glycine. While this variant is present in population databases (rs779169075), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with DNMT1-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. 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. 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. |