rs199473690

Variant names:

• chr19-10155017-T-C
• rs199473690
• NM_001130823.3:c.1532A>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001130823.3(DNMT1):​c.1532A>G​(p.Tyr511Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:2
• Conservation: PhyloP100: 7.99

Genes affected

DNMT1 (HGNC:2976): (DNA methyltransferase 1) This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA. This protein is the major enzyme responsible for maintaining methylation patterns following DNA replication and shows a preference for hemi-methylated DNA. Methylation of DNA is an important component of mammalian epigenetic gene regulation. Aberrant methylation patterns are found in human tumors and associated with developmental abnormalities. Variation in this gene has been associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 19-10155017-T-C is Pathogenic according to our data. Variant chr19-10155017-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10155017-T-C is described in Lovd as [Pathogenic]. Variant chr19-10155017-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1532A>G	p.Tyr511Cys	missense_variant	Exon 20 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1484A>G	p.Tyr495Cys	missense_variant	Exon 19 of 40		NP_001305659.1
DNMT1	NM_001379.4	c.1484A>G	p.Tyr495Cys	missense_variant	Exon 19 of 40		NP_001370.1
DNMT1	NM_001318731.2	c.1169A>G	p.Tyr390Cys	missense_variant	Exon 20 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1532A>G	p.Tyr511Cys	missense_variant	Exon 20 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Pathogenic:4 Uncertain:1

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Nov 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Feb 26, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 30, 2013

UCLA Clinical Genomics Center, UCLA

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant cerebellar ataxia, deafness and narcolepsy Pathogenic:1

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Pathogenic:1

Jul 23, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Charcot-Marie-Tooth disease Uncertain:1

-

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.1	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.55		Loss of phosphorylation at Y495 (P = 0.0337);.;
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.8
Varity_R		0.91
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473690; hg19: chr19-10265693;