NM_001130823.3(DNMT1):c.3036C>G (p.Ile1012Met) AND Hereditary sensory neuropathy-deafness-dementia syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 7, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001127316.8

Allele description [Variation Report for NM_001130823.3(DNMT1):c.3036C>G (p.Ile1012Met)]

NM_001130823.3(DNMT1):c.3036C>G (p.Ile1012Met)

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.3036C>G (p.Ile1012Met)

HGVS:

NC_000019.10:g.10143846G>C
NG_028016.3:g.92441C>G
NM_001130823.3:c.3036C>GMANE SELECT
NM_001318730.2:c.2988C>G
NM_001318731.2:c.2673C>G
NM_001379.4:c.2988C>G
NP_001124295.1:p.Ile1012Met
NP_001305659.1:p.Ile996Met
NP_001305660.1:p.Ile891Met
NP_001370.1:p.Ile996Met
LRG_362t1:c.3036C>G
LRG_362:g.92441C>G
NC_000019.9:g.10254522G>C
NC_000019.9:g.10254522G>C
NM_001130823.1:c.3036C>G
NM_001379.2:c.2988C>G

Protein change:

I1012M

Links:

dbSNP: rs376854079

NCBI 1000 Genomes Browser:

rs376854079

Molecular consequence:

NM_001130823.3:c.3036C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318730.2:c.2988C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001318731.2:c.2673C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001379.4:c.2988C>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
SCV001286612	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV003281844	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 7, 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

SCV001286612

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Likely benign
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV003281844

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 7, 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 Illumina Laboratory Services, Illumina, SCV001286612.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003281844.2

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

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 891808). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. This variant is present in population databases (rs376854079, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1012 of the DNMT1 protein (p.Ile1012Met).

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine