VCV000374875.3 - ClinVar

NM_014727.3(KMT2B):c.1690C>T (p.Arg564Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic
Pathogenic (1); Likely pathogenic (1)

2 out of 3 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_014727.3(KMT2B):c.1690C>T (p.Arg564Ter)

Variation ID: 374875 Accession: VCV000374875.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19q13.12 19: 35721037 (GRCh38) [ NCBI UCSC ] 19: 36211939 (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	Jan 23, 2017	Nov 14, 2020	Mar 1, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_014727.3:c.1690C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_055542.1:p.Arg564Ter	nonsense
NC_000019.10:g.35721037C>T
NC_000019.9:g.36211939C>T
NG_052906.1:g.8019C>T

Protein change

R564*

Other names

NM_014727.2:n.1690C>T(p.Arg564Ter)

Canonical SPDI

NC_000019.10:35721036:C:T

Global minor allele frequency (GMAF) Help The 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

ClinGen: CA16043951 OMIM: 606834.0006 dbSNP: rs1057519283 VarSome

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
Gene	OMIM	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.
KMT2B		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2590	2657

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.
Dystonia 28, childhood-onset	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 1, 2020	RCV000415564.4

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.	Expand all rows Collapse all rows 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.
Likely pathogenic (Apr 16, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Dystonia 28, childhood-onset	SIB Swiss Institute of Bioinformatics Accession: SCV000787443.1 First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018	Publications: PubMed (1) PubMed: 27992417 Comment: show This variant is interpreted as a Likely Pathogenic, for Dystonia 28, childhood-onset, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:27992417). (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Mar 01, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Dystonia 28, childhood-onset (Autosomal dominant inheritance)	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001443035.1 First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020	Comment: show Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PVS1,PS2,PM2 (less) Observation: 1 Collection method: clinical testing Allele origin: de novo Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: de novo Affected status: yes Clinical Features: severe ID (present) , muscular hypotonia (present)

Pathogenic (Feb 01, 2017) N Not contributing to aggregate classification	no assertion criteria provided	DYSTONIA 28, CHILDHOOD-ONSET	OMIM Accession: SCV000493961.2 First in ClinVar: Jan 23, 2017 Last updated: Jan 23, 2017	Publications: PubMed (1) PubMed: 27992417 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In a 6-year-old girl (patient 12) with childhood-onset dystonia-28 (DYT28; 617284), Meyer et al. (2017) identified a de novo heterozygous c.1690C-T transition (c.1690C-T, NM_014727.2) in … (more) In a 6-year-old girl (patient 12) with childhood-onset dystonia-28 (DYT28; 617284), Meyer et al. (2017) identified a de novo heterozygous c.1690C-T transition (c.1690C-T, NM_014727.2) in exon 3 of the KMT2B gene, resulting in an arg564-to-ter (R564X) substitution. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in haploinsufficiency. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. (less)

Comment:

This variant is interpreted as a Likely Pathogenic, for Dystonia 28, childhood-onset, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:27992417).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.	Meyer E	Nature genetics	2017	PMID: 27992417

Text-mined citations for rs1057519283 ...

These 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 Apr 13, 2026