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.
ClinVar Genomic variation as it relates to human health
NM_001130823.3(DNMT1):c.1532A>G (p.Tyr511Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(8)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001130823.3(DNMT1):c.1532A>G (p.Tyr511Cys)
Variation ID: 29682 Accession: VCV000029682.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 10155017 (GRCh38) [ NCBI UCSC ] 19: 10265693 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 11, 2015 Nov 24, 2024 Oct 8, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001130823.3:c.1532A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001124295.1:p.Tyr511Cys missense NM_001318730.2:c.1484A>G NP_001305659.1:p.Tyr495Cys missense NM_001318731.2:c.1169A>G NP_001305660.1:p.Tyr390Cys missense NM_001379.4:c.1484A>G NP_001370.1:p.Tyr495Cys missense NC_000019.10:g.10155017T>C NC_000019.9:g.10265693T>C NG_028016.3:g.81270A>G LRG_362:g.81270A>G LRG_362t1:c.1532A>G LRG_362p1:p.Tyr511Cys - Protein change
- Y495C, Y511C, Y390C
- Other names
- -
- Canonical SPDI
- NC_000019.10:10155016:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| DNMT1 | - | - |
GRCh38 GRCh37 |
1306 | 1453 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Oct 8, 2024 | RCV000022529.39 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 23, 2021 | RCV000236669.3 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV000789093.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 1, 2022 | RCV002283444.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
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Likely pathogenic
(Jul 30, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
NEUROPATHY, HEREDITARY SENSORY, TYPE IE
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000255360.2 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 40-49 years
Sex: female
Ethnicity/Population group: European Caucasian
Testing laboratory: UCLA Clinical Genomics Center
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant cerebellar ataxia, deafness and narcolepsy
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572702.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Cerebellar ataxia (present) , Peripheral neuropathy (present)
|
|
|
Pathogenic
(Jul 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000292544.12
First in ClinVar: Jul 25, 2016 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
|
|
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Pathogenic
(Nov 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary sensory neuropathy-deafness-dementia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001583990.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
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Pathogenic
(Oct 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary sensory neuropathy-deafness-dementia syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005400642.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with cerebellar ataxia, deafness, and narcolepsy (MIM#604121) and hereditary sensory neuropathy, type IE (MIM#614116). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated cytosine specific DNA methyltransferase replication foci domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in three unrelated families with affected heterozygous individuals with hereditary sensory neuropathy (PMID: 21532572). This variant has also been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. In vitro functional studies show this variant affects proper folding of DMNT1, and results in premature protein degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation (PMID: 21532572). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
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Pathogenic
(Feb 26, 2013)
|
no assertion criteria provided
Method: literature only
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NEUROPATHY, HEREDITARY SENSORY, TYPE IE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000043818.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In affected members of 2 large American kindreds and 1 Japanese kindred with autosomal dominant inheritance of hereditary sensory neuropathy type IE (HSN1E; 614116) with … (more)
In affected members of 2 large American kindreds and 1 Japanese kindred with autosomal dominant inheritance of hereditary sensory neuropathy type IE (HSN1E; 614116) with sensorineural hearing loss and early-onset dementia, Klein et al. (2011) identified a heterozygous 1484A-G transition in exon 20 of the DNMT1 gene, resulting in a tyr495-to-cys (Y495C) substitution. The mutation occurred in the targeting-sequence domain of the protein, in the N-terminal regulatory region required for enzymatic function. The mutation was not found in over 1,500 controls. Two of the kindreds had previously been reported by Wright and Dyck (1995) and Hojo et al. (1999), respectively. In vitro functional expression studies in E. coli and HeLa cells showed that the mutation affected proper folding of DNMT1 and resulted in premature protein degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation. These changes indicated epigenetic dysregulation. Klein et al. (2013) identified a heterozygous Y495C mutation in affected members of a family from Scotland with HSN1E. A family of Norwegian origin with the same phenotype was found to carry a different mutation affecting the same codon (Y495H; 126375.0006), suggesting a mutation hotspot. (less)
|
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Uncertain significance
(-)
|
no assertion criteria provided
Method: literature only
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium
Accession: SCV000928444.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
|
|
|
Uncertain significance
(Jan 06, 2016)
|
no assertion criteria provided
Method: literature only
|
Hereditary sensory neuropathy-deafness-dementia syndrome
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174779.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
|
Comment:
Comment:
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)
Comment:
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.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with cerebellar ataxia, deafness, and narcolepsy (MIM#604121) and hereditary sensory neuropathy, type IE (MIM#614116). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated cytosine specific DNA methyltransferase replication foci domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in three unrelated families with affected heterozygous individuals with hereditary sensory neuropathy (PMID: 21532572). This variant has also been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. In vitro functional studies show this variant affects proper folding of DMNT1, and results in premature protein degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation (PMID: 21532572). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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)
Comment:
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.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with cerebellar ataxia, deafness, and narcolepsy (MIM#604121) and hereditary sensory neuropathy, type IE (MIM#614116). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated cytosine specific DNA methyltransferase replication foci domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in three unrelated families with affected heterozygous individuals with hereditary sensory neuropathy (PMID: 21532572). This variant has also been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. In vitro functional studies show this variant affects proper folding of DMNT1, and results in premature protein degradation, reduced methyltransferase activity, and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site-specific hypermethylation (PMID: 21532572). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| DNMT1 mutations found in HSANIE patients affect interaction with UHRF1 and neuronal differentiation. | Smets M | Human molecular genetics | 2017 | PMID: 28334952 |
| Defects of mutant DNMT1 are linked to a spectrum of neurological disorders. | Baets J | Brain : a journal of neurology | 2015 | PMID: 25678562 |
| Clinical exome sequencing for genetic identification of rare Mendelian disorders. | Lee H | JAMA | 2014 | PMID: 25326637 |
| DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss. | Klein CJ | Neurology | 2013 | PMID: 23365052 |
| Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. | Klein CJ | Nature genetics | 2011 | PMID: 21532572 |
| Hereditary sensory neuropathy with deafness and dementia: a clinical and neuroimaging study. | Hojo K | European journal of neurology | 1999 | PMID: 10210919 |
| Hereditary sensory neuropathy with sensorineural deafness and early-onset dementia. | Wright A | Neurology | 1995 | PMID: 7898717 |
Text-mined citations for rs199473690 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.