ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.1532A>G (p.Tyr511Cys)

dbSNP: rs199473690
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000022529 SCV000255360 likely pathogenic Hereditary sensory neuropathy-deafness-dementia syndrome 2013-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000236669 SCV000292544 pathogenic not provided 2021-07-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect showing degradation compared to wild-type DNMT protein (Baets et al., 2015); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21532572, 25678562, 25942534, 23521649, 26747177, 23365052)
Invitae RCV000022529 SCV001583990 pathogenic Hereditary sensory neuropathy-deafness-dementia syndrome 2023-11-20 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 511 of the DNMT1 protein (p.Tyr511Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hereditary sensory neuropathy, dementia and hearing loss (PMID: 21532572, 25326637, 25678562). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Tyr495Cys. ClinVar contains an entry for this variant (Variation ID: 29682). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNMT1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNMT1 function (PMID: 21532572, 28334952). For these reasons, this variant has been classified as Pathogenic.
3billion RCV002283444 SCV002572702 pathogenic Autosomal dominant cerebellar ataxia, deafness and narcolepsy 2022-09-01 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence that the variant has a damaging effect on the gene or gene product (PMID: 21532572). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with solid evidence (ClinVar ID: VCV000029682). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 21532572 , 23365052). A different missense change at the same codon (p.Tyr511His) has been reported to be associated with DNMT1-related disorder (ClinVar ID: VCV000162188 / PMID: 23365052). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000022529 SCV000043818 pathogenic Hereditary sensory neuropathy-deafness-dementia syndrome 2013-02-26 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789093 SCV000928444 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only
Inherited Neuropathy Consortium Ii, University Of Miami RCV000022529 SCV004174779 uncertain significance Hereditary sensory neuropathy-deafness-dementia syndrome 2016-01-06 no assertion criteria provided literature only

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