Submissions for variant NM_001130823.3(DNMT1):c.1080G>A (p.Met360Ile)

dbSNP: rs1064796441

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478729	SCV000573164	uncertain significance	not provided	2017-02-13	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the DNMT1 gene. The M360I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The M360I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M360I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved and in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001856874	SCV002299809	uncertain significance	Hereditary sensory neuropathy-deafness-dementia syndrome	2021-02-19	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DNMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423461). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 360 of the DNMT1 protein (p.Met360Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine.