Submissions for variant NM_001130823.3(DNMT1):c.3524-5G>T

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003324421	SCV004029266	uncertain significance	not specified	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: DNMT1 c.3524-5G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 249566 control chromosomes, predominantly at a frequency of 0.00014 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3524-5G>T in individuals affected with Hereditary Sensory Neuropathy-Deafness Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2577344). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003528459	SCV004303980	uncertain significance	Hereditary sensory neuropathy-deafness-dementia syndrome	2023-09-29	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 2577344). This sequence change falls in intron 32 of the DNMT1 gene. It does not directly change the encoded amino acid sequence of the DNMT1 protein. This variant is present in population databases (rs761815960, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions.
PreventionGenetics, part of Exact Sciences	RCV003946490	SCV004760522	likely benign	DNMT1-related disorder	2019-04-23	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).