Submissions for variant NM_001130823.3(DNMT1):c.406C>T (p.Arg136Cys)

gnomAD frequency: 0.00024  dbSNP: rs138841970

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000996738	SCV000279276	likely benign	not provided	2020-02-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000549690	SCV000410264	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.
Invitae	RCV000549690	SCV000651308	uncertain significance	Hereditary sensory neuropathy-deafness-dementia syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 136 of the DNMT1 protein (p.Arg136Cys). This variant is present in population databases (rs138841970, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Beckwith-Wiedemann syndrome (PMID: 30165906). ClinVar contains an entry for this variant (Variation ID: 234461). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000996738	SCV001151625	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	DNMT1: BP4, BS1
Ambry Genetics	RCV002321845	SCV002631994	likely benign	Inborn genetic diseases	2019-08-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000625705	SCV000599434	uncertain significance	Beckwith-Wiedemann syndrome		no assertion criteria provided	research	This variant was identified in heterozygous form in 1 of 51 cases with Beckwith Wiedemann syndrome with loss of methylation at KCNQ1OT1 at Imprinting centre 2 on 11p15.5. The variant was maternally inherited. The variant frequency in dbSNP147 is 0.00028.