ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.2693C>T (p.Thr898Ile) (rs201213597)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235408 SCV000293762 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing The T898I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T898I variant is observed in 67/30782 (0.2%) alleles from individuals of South Asian background, which is greater than expected for this disorder (Lek et al., 2016). The T898I 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. 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 RCV001088607 SCV000410227 benign Hereditary sensory neuropathy type IE 2018-01-12 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 RCV000235408 SCV000885310 likely benign not provided 2018-05-07 criteria provided, single submitter clinical testing The c.2693C>T p.Thr898Ile variant (rs201213597), 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 a South Asian population frequency of 0.2% (identified on 67 out of 30,782 chromosomes). The threonine at position 898 is moderately conserved, considering 12 species, and computational analyses of the effects of the p.Thr898Ile variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the p.Thr898Ile variant is likely to be benign.
Invitae RCV001088607 SCV001020731 likely benign Hereditary sensory neuropathy type IE 2019-12-31 criteria provided, single submitter clinical testing

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