Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28991257, 22126750, 23320472, 31935506, 27302555, 28884922, 24739679, 32978145, 32368696, 33084842, 37043208, 33057194, 35904121, 31941532, 36891680, 37810849, 35982159)
NM_003482.4(KMT2D):c.12592C>T (p.Arg4198Ter)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
Pathogenic (7)
Pathogenic (7)
7 out of 8 submissions contributed to this classification
Help
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.
8
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003482.4(KMT2D):c.12592C>T (p.Arg4198Ter)
Variation ID: 158722 Accession: VCV000158722.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.12 12: 49425896 (GRCh37) [ NCBI UCSC ] 12: 49032113 (GRCh38) [ 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 Nov 23, 2014 May 16, 2026 Aug 18, 2025 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003482.4:c.12592C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003473.3:p.Arg4198Ter nonsense NC_000012.12:g.49032113G>A NC_000012.11:g.49425896G>A NG_027827.1:g.28212C>T - Protein change
- R4198*
- Other names
- -
- Canonical SPDI
- NC_000012.12:49032112:G:A
-
Global minor allele
frequency (GMAF) HelpThe 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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| KMT2D | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7200 | 7492 | |
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. |
|---|---|---|---|---|
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 2, 2025 | RCV000146159.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 27, 2017 | RCV000624920.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 10, 2018 | RCV000707588.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 18, 2025 | RCV001548390.4 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Aug 18, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV001768292.2
First in ClinVar: Aug 07, 2021 Last updated: Aug 30, 2025 |
Comment:
show
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28991257, 22126750, 23320472, 31935506, 27302555, 28884922, 24739679, 32978145, 32368696, 33084842, 37043208, 33057194, 35904121, 31941532, 36891680, 37810849, 35982159) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Aug 22, 2013)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Kabuki syndrome 1
(Autosomal dominant inheritance)
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000193384.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Nov 01, 2016)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Kabuki syndrome 1 |
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781655.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 27, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Inborn genetic diseases |
Ambry Genetics
Accession: SCV000742681.4
First in ClinVar: Apr 15, 2018 Last updated: Apr 13, 2025 |
Observation:
2
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Ashkenazi Jewish/Caucasian/Yemeni/Argentinian
Observation 2
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Caucasian/Polish
|
|
|
Pathogenic
(Oct 31, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Kabuki syndrome 1 |
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893301.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(May 10, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Kabuki syndrome |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000836689.6
First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026 |
Comment:
show
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). This variant has been observed in several individuals affected with Kabuki syndrome (PMID: 28295206, 26300940, 23320472, 27302555). ClinVar contains an entry for this variant (Variation ID: 158722). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg4198*) in the KMT2D gene. It is expected to result in an absent or disrupted protein product. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jun 02, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Kabuki syndrome 1
(Autosomal dominant inheritance)
|
Variantyx, Inc.
Accession: SCV007593814.1
First in ClinVar: May 16, 2026 Last updated: May 16, 2026 |
Comment:
show
This is a nonsense variant in the KMT2D gene (OMIM: 602113). Pathogenic variants in this gene have been associated with autosomal dominant Kabuki syndrome 1. This variant likely occurred de novo in the current proband and individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 37810849, 28991257, 37043208) (PS2_Very_Strong). The alteration introduces a premature termination codon in exon 40 out of 55 and is expected to result in loss of function, which is a known disease mechanism for KMT2D in this disorder (PMID: 20711175, 21671394, 21607748) (PVS1). It has been reported in at least four affected individuals (PMID: 26300940, 37810849, 28991257, 37043208) (PS4) but it is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant Kabuki syndrome 1. (less)
Observation: 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
|
|
|
Pathogenic
(Jun 05, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Kabuki syndrome 1 |
Autoinflammatory diseases unit, CHU de Montpellier
Accession: SCV001438126.2
First in ClinVar: Oct 23, 2020 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: de novo
Affected status: yes
Sex: male
|
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). This variant has been observed in several individuals affected with Kabuki syndrome (PMID: 28295206, 26300940, 23320472, 27302555). ClinVar contains an entry for this variant (Variation ID: 158722). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg4198*) in the KMT2D gene. It is expected to result in an absent or disrupted protein product.
Comment:
This is a nonsense variant in the KMT2D gene (OMIM: 602113). Pathogenic variants in this gene have been associated with autosomal dominant Kabuki syndrome 1. This variant likely occurred de novo in the current proband and individuals reported in the published literature; however, the possibility of parental germline mosaicism cannot be excluded (PMID: 37810849, 28991257, 37043208) (PS2_Very_Strong). The alteration introduces a premature termination codon in exon 40 out of 55 and is expected to result in loss of function, which is a known disease mechanism for KMT2D in this disorder (PMID: 20711175, 21671394, 21607748) (PVS1). It has been reported in at least four affected individuals (PMID: 26300940, 37810849, 28991257, 37043208) (PS4) but it is absent from control populations (https://gnomad.broadinstitute.org/) (PM2). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant Kabuki syndrome 1.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical and molecular analysis of Guangxi patients with Kabuki syndrome and KMT2D mutations. | Yi S | Heliyon | 2023 | PMID: 37810849 |
| Characterizing the molecular impact of KMT2D variants on the epigenetic and transcriptional landscapes in Kabuki syndrome. | Jung YL | Human molecular genetics | 2023 | PMID: 37043208 |
| Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. | Jin SC | Nature genetics | 2017 | PMID: 28991257 |
| Molecular, clinical and neuropsychological study in 31 patients with Kabuki syndrome and KMT2D mutations. | Lehman N | Clinical genetics | 2017 | PMID: 28295206 |
| Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2. | Bögershausen N | Human mutation | 2016 | PMID: 27302555 |
| The strong association of left-side heart anomalies with Kabuki syndrome. | Yoon JK | Korean journal of pediatrics | 2015 | PMID: 26300940 |
| Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with Kabuki syndrome. | Cheon CK | Journal of human genetics | 2014 | PMID: 24739679 |
| MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study. | Makrythanasis P | Clinical genetics | 2013 | PMID: 23320472 |
| How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. | Banka S | European journal of human genetics : EJHG | 2012 | PMID: 22126750 |
| Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. | Hannibal MC | American journal of medical genetics. Part A | 2011 | PMID: 21671394 |
| A mutation screen in patients with Kabuki syndrome. | Li Y | Human genetics | 2011 | PMID: 21607748 |
| Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. | Ng SB | Nature genetics | 2010 | PMID: 20711175 |
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Text-mined citations for rs587783685 ...
HelpThese 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 May 16, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.