ClinVar Miner

Submissions for variant NM_001130823.3(DNMT1):c.1532A>G (p.Tyr511Cys) (rs199473690)

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Total submissions: 5
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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 type IE 2013-07-30 criteria provided, single submitter clinical testing
GeneDx RCV000236669 SCV000292544 pathogenic not provided 2016-04-12 criteria provided, single submitter clinical testing The Y511C missense pathogenic variant in the DNMT1 gene has been reported previously, using alternative nomenclature of Y495C, in association with hereditary sensory and autonomic neuropathy with dementia and hearing loss (HSAN1E) (Klein et al., 2011; Klein et al., 2013). Functional studies show Y511C alters protein folding and degradation, enzyme activity, and impairs heterochromatin binding leading to abnormal methylation (Klein et al., 2011). Additionally, a different amino acid substitution at the same position (Y511H, reported using alternative nomenclature of Y495H) has also been reported, and the Y511 residue has been identified as a mutation hotspot associated with the HSAN1E phenotype (Klein et al., 2013). The Y511C variant is a non-conservative amino acid substitution that alters a conserved position in the targeting sequence domain. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, the presence of the Y511C is consistent with a diagnosis of HSAN1E
Invitae RCV000022529 SCV001583990 pathogenic Hereditary sensory neuropathy type IE 2020-02-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 511 of the DNMT1 protein (p.Tyr511Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hereditary sensory neuropathy, dementia and hearing loss (PMID: 21532572, 25678562, 25326637). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Tyr495Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 29682). This variant has been reported to affect DNMT1 protein function (PMID: 21532572, 28334952). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000022529 SCV000043818 pathogenic Hereditary sensory neuropathy type IE 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

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