Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001378601 | SCV001576204 | likely pathogenic | Hereditary sensory neuropathy-deafness-dementia syndrome | 2020-06-19 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine with serine at codon 540 of the DNMT1 protein (p.Tyr540Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of hereditary sensory and autonomic neuropathy (Invitae). In at least one individual the variant was observed to be de novo. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Tyr540 amino acid residue in DNMT1. Other variant(s) that disrupt this residue have been observed in individuals with DNMT1-related conditions (PMID: 25678562, 30342480), which suggests that this may be a clinically significant amino acid residue. 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. |