ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.1008G>A (p.Lys336=)

gnomAD frequency: 0.00001  dbSNP: rs750048459
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001370813 SCV001567353 uncertain significance Hereditary sensory neuropathy-deafness-dementia syndrome 2023-11-02 criteria provided, single submitter clinical testing This sequence change affects codon 336 of the DNMT1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DNMT1 protein. This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. This variant is present in population databases (rs750048459, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1061265). Variants that disrupt 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. 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.
Ambry Genetics RCV002377550 SCV002690647 uncertain significance Inborn genetic diseases 2020-11-19 criteria provided, single submitter clinical testing The c.960G>A variant (also known as p.K320K), located in coding exon 12 of the DNMT1 gene, results from a G to A substitution at nucleotide position 960. This nucleotide substitution does not change the lysine at codon 320. This change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing, however, loss of function of DNMT1 has not been established as the mechanism of disease. This nucleotide position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV002476693 SCV002780011 uncertain significance Autosomal dominant cerebellar ataxia, deafness and narcolepsy; Hereditary sensory neuropathy-deafness-dementia syndrome 2021-07-22 criteria provided, single submitter clinical testing

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