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

dbSNP: rs199473690

Total submissions: 7

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)
Labcorp Genetics (formerly Invitae), Labcorp	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