Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001127316 | SCV001286612 | likely benign | Hereditary sensory neuropathy-deafness-dementia syndrome | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. |
| Ambry Genetics | RCV002436715 | SCV002750670 | uncertain significance | Inborn genetic diseases | 2021-06-08 | criteria provided, single submitter | clinical testing | The p.I996M variant (also known as c.2988C>G), located in coding exon 28 of the DNMT1 gene, results from a C to G substitution at nucleotide position 2988. The isoleucine at codon 996 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV001127316 | SCV003281844 | uncertain significance | Hereditary sensory neuropathy-deafness-dementia syndrome | 2023-03-07 | criteria provided, single submitter | clinical testing | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNMT1 protein function. ClinVar contains an entry for this variant (Variation ID: 891808). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. This variant is present in population databases (rs376854079, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1012 of the DNMT1 protein (p.Ile1012Met). |