NM_001130823.3(DNMT1):c.1609G>A (p.Asp537Asn) AND Hereditary sensory neuropathy-deafness-dementia syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 17, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003640828.1

Allele description

NM_001130823.3(DNMT1):c.1609G>A (p.Asp537Asn)

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.1609G>A (p.Asp537Asn)

HGVS:

NC_000019.10:g.10154940C>T
NG_028016.3:g.81347G>A
NM_001130823.3:c.1609G>AMANE SELECT
NM_001318730.2:c.1561G>A
NM_001318731.2:c.1246G>A
NM_001379.4:c.1561G>A
NP_001124295.1:p.Asp537Asn
NP_001124295.1:p.Asp537Asn
NP_001305659.1:p.Asp521Asn
NP_001305660.1:p.Asp416Asn
NP_001370.1:p.Asp521Asn
LRG_362t1:c.1609G>A
LRG_362:g.81347G>A
LRG_362p1:p.Asp537Asn
NC_000019.9:g.10265616C>T
NM_001130823.1:c.1609G>A

Protein change:

D416N

Molecular consequence:

NM_001130823.3:c.1609G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318730.2:c.1561G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318731.2:c.1246G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379.4:c.1561G>A - 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

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Chain G, Complex of Escherichia coli DNA Adenine Methyltransferase (DAM) with Ad...
Chain G, Complex of Escherichia coli DNA Adenine Methyltransferase (DAM) with AdoHcy and with DNA Containing Proximal Pap Regulon Sequence
gi|808043056|pdb|4RTN|G

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004509351	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004509351

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 17, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV004509351.1

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 537 of the DNMT1 protein (p.Asp537Asn). This variant is present in population databases (rs767797868, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. 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 not expected to disrupt DNMT1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

Last Updated: Feb 28, 2024

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