ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.4876G>A (p.Glu1626Lys) (rs201774098)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235768 SCV000293365 uncertain significance not specified 2015-11-21 criteria provided, single submitter clinical testing The E1626K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The E1626K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position outside of the targeting sequence domain that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV001084724 SCV000410210 benign Hereditary sensory neuropathy type IE 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757172 SCV000885307 uncertain significance not provided 2018-02-02 criteria provided, single submitter clinical testing The DNMT1 c.4876G>A; p.Glu1626Lys variant (rs201774098), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.02% (identified on 45 out of 211,492 chromosomes) and is classified as a variant of uncertain significance in ClinVar (ID: 246060). The glutamic acid at position 1626 is moderately conserved, considering 12 species and computational analyses of the effects of the p.Glu1626Lys variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Glu1626Lys variant cannot be determined with certainty.
Invitae RCV001084724 SCV001107362 likely benign Hereditary sensory neuropathy type IE 2019-12-31 criteria provided, single submitter clinical testing

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