Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000810355 | SCV000950551 | pathogenic | Hereditary sensory neuropathy-deafness-dementia syndrome | 2022-02-03 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro507 amino acid residue in DNMT1. Other variant(s) that disrupt this residue have been observed in individuals with DNMT1-related conditions (PMID: 21532572, 24727570, 25678562), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects DNMT1 function (PMID: 31049076). 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"). ClinVar contains an entry for this variant (Variation ID: 654394). This missense change has been observed in individual(s) with hereditary sensory and autonomic neuropathy type 1E (PMID: 25678562; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 507 of the DNMT1 protein (p.Pro507Leu). |
| Ambry Genetics | RCV002390631 | SCV002701066 | uncertain significance | Inborn genetic diseases | 2020-01-16 | criteria provided, single submitter | clinical testing | The p.P491L variant (also known as c.1472C>T), located in coding exon 19 of the DNMT1 gene, results from a C to T substitution at nucleotide position 1472. The proline at codon 491 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This alteration was reported in a patient with progressive hearing loss and progressive sensory loss. Nerve conduction studies showed severe pure sensory axonal neuropathy, and a sural nerve biopsy revealed loss of myelinated and unmyelinated fibers. (Baets J et al. Brain, 2015 Apr;138:845-61). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Inherited Neuropathy Consortium Ii, |
RCV000810355 | SCV004174775 | uncertain significance | Hereditary sensory neuropathy-deafness-dementia syndrome | 2016-01-06 | no assertion criteria provided | literature only |