NM_001130823.3(DNMT1):c.1532A>G (p.Tyr511Cys) AND Hereditary sensory neuropathy-deafness-dementia syndrome

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Oct 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000022529.39

Allele description [Variation Report for NM_001130823.3(DNMT1):c.1532A>G (p.Tyr511Cys)]

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

Gene:

DNMT1:DNA methyltransferase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

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

HGVS:

NC_000019.10:g.10155017T>C
NG_028016.3:g.81270A>G
NM_001130823.3:c.1532A>GMANE SELECT
NM_001318730.2:c.1484A>G
NM_001318731.2:c.1169A>G
NM_001379.4:c.1484A>G
NP_001124295.1:p.Tyr511Cys
NP_001305659.1:p.Tyr495Cys
NP_001305660.1:p.Tyr390Cys
NP_001370.1:p.Tyr495Cys
LRG_362t1:c.1532A>G
LRG_362:g.81270A>G
LRG_362p1:p.Tyr511Cys
NC_000019.9:g.10265693T>C
NM_001130823.1:c.1532A>G
NM_001379.2:c.1484A>G

Protein change:

Y390C; TYR495CYS

Links:

OMIM: 126375.0001; dbSNP: rs199473690

NCBI 1000 Genomes Browser:

rs199473690

Molecular consequence:

NM_001130823.3:c.1532A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318730.2:c.1484A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318731.2:c.1169A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001379.4:c.1484A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary sensory neuropathy-deafness-dementia syndrome
Synonyms:: HSN IE; NEUROPATHY, HEREDITARY SENSORY, WITH HEARING LOSS AND DEMENTIA; Hereditary sensory neuropathy type IE
Identifiers:: MONDO: MONDO:0013584; MedGen: C3279885; Orphanet: 456318; OMIM: 614116

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000043818	OMIM	no assertion criteria provided	Pathogenic (Feb 26, 2013)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 21532572, 7898717, 10210919, 23365052
SCV000255360	UCLA Clinical Genomics Center, UCLA - CES	criteria provided, single submitter (Lee et al. (JAMA. 2014))	Likely pathogenic (Jul 30, 2013)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001583990	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25326637, 25678562, 21532572, 28334952, 28492532
SCV004174779	Inherited Neuropathy Consortium Ii, University Of Miami	no assertion criteria provided	Uncertain significance (Jan 6, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV005400642	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 8, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21532572, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only, clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
European Caucasian	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hereditary sensory neuropathy with sensorineural deafness and early-onset dementia.

Wright A, Dyck PJ.

Neurology. 1995 Mar;45(3 Pt 1):560-2.

PubMed [citation]

PMID:: 7898717

Hereditary sensory neuropathy with deafness and dementia: a clinical and neuroimaging study.

Hojo K, Imamura T, Takanashi M, Ishii K, Sasaki M, Imura S, Ozono R, Takatsuki Y, Takauchi S, Mori E.

Eur J Neurol. 1999 May;6(3):357-61.

PubMed [citation]

PMID:: 10210919

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000043818.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UCLA Clinical Genomics Center, UCLA - CES, SCV000255360.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European Caucasian	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001583990.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Inherited Neuropathy Consortium Ii, University Of Miami, SCV004174779.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005400642.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 30, 2024

ClinVar

Relating variation to medicine