Submissions for variant NM_001130823.3(DNMT1):c.3668G>A (p.Arg1223His)

gnomAD frequency: 0.00001  dbSNP: rs757460628

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000813215	SCV000953561	uncertain significance	Hereditary sensory neuropathy-deafness-dementia syndrome	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1223 of the DNMT1 protein (p.Arg1223His). This variant is present in population databases (rs757460628, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 438391). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DNMT1 protein function with a negative predictive value of 80%. 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.
Illumina Laboratory Services, Illumina	RCV000813215	SCV001283153	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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV002225636	SCV002504642	likely benign	not provided	2020-11-11	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Ambry Genetics	RCV002460080	SCV002617977	likely benign	Inborn genetic diseases	2021-11-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetics and Molecular Pathology Laboratory, Hudson Institute of Medical Research	RCV000625706	SCV000599436	uncertain significance	Beckwith-Wiedemann syndrome		no assertion criteria provided	research	This variant was identified in heterozygous form in 1 of 53 cases with Beckwith Wiedemann syndrome with loss of KCNQ1OT1 at Imprinting centre 2 on 11p15.5. The variant frequency in dbSNP is 0.00002.