ClinVar Genomic variation as it relates to human health
NM_003482.4(KMT2D):c.16501C>T (p.Arg5501Ter)
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.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003482.4(KMT2D):c.16501C>T (p.Arg5501Ter)
Variation ID: 280126 Accession: VCV000280126.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q13.12 12: 49022063 (GRCh38) [ NCBI UCSC ] 12: 49415846 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 7, 2017 Feb 20, 2024 Jun 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003482.4:c.16501C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003473.3:p.Arg5501Ter nonsense NC_000012.12:g.49022063G>A NC_000012.11:g.49415846G>A NG_027827.1:g.38262C>T - Protein change
- R5501*
- Other names
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- Canonical SPDI
- NC_000012.12:49022062:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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KMT2D | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5250 | 5462 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 6, 2023 | RCV000283712.5 | |
Pathogenic (3) |
criteria provided, single submitter
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- | RCV000578361.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 4, 2022 | RCV000557296.8 |
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
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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
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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. |
More information
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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. |
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Pathogenic
(Aug 14, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329990.6
First in ClinVar: Dec 06, 2016 Last updated: Jan 07, 2017 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 37 amino acids are lost; Not observed in large population cohorts … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 37 amino acids are lost; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20711175, 25525159, 27302555, 28884922, 29568095) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Kabuki syndrome 1
Affected status: yes
Allele origin:
unknown
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3billion
Accession: SCV004013460.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 27302555). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 27302555, 28884922). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000280126/PMID: 20711175). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Oligohydramnios (present) , Unilateral cleft lip (present) , Unilateral cleft palate (present) , Orofacial cleft (present) , Abnormal facial shape (present) , Microphthalmia (present) , … (more)
Oligohydramnios (present) , Unilateral cleft lip (present) , Unilateral cleft palate (present) , Orofacial cleft (present) , Abnormal facial shape (present) , Microphthalmia (present) , Corneal opacity (present) , Anterior segment dysgenesis (present) , Abnormal posterior eye segment morphology (present) , Ptosis (present) , Astigmatism (present) , Perimembranous ventricular septal defect (present) , Ventricular septal defect (present) , Global developmental delay (present) , Failure to thrive (present) , Sparse hair (present) , Sparse lateral eyebrow (present) , Wide nasal bridge (present) , Depressed nasal bridge (present) , Single transverse palmar crease (present) (less)
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Pathogenic
(Jun 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004236909.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Kabuki syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000636651.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 280126). This premature translational stop signal has been observed in individual(s) with clinical features of Kabuki syndrome (PMID: 2071175, 28884922). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg5501*) in the KMT2D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the KMT2D protein. (less)
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Pathogenic
(Jul 12, 2017)
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no assertion criteria provided
Method: clinical testing
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Kabuki syndrome 1
Affected status: yes
Allele origin:
de novo
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Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV000680121.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
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Pathogenic
(Apr 30, 2015)
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no assertion criteria provided
Method: clinical testing
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Kabuki syndrome 1
Affected status: yes
Allele origin:
unknown
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Autoinflammatory diseases unit, CHU de Montpellier
Accession: SCV001438163.1
First in ClinVar: Oct 23, 2020 Last updated: Oct 23, 2020 |
Sex: female
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Congenital heart defects in molecularly proven Kabuki syndrome patients. | Digilio MC | American journal of medical genetics. Part A | 2017 | PMID: 28884922 |
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 |
Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. | Ng SB | Nature genetics | 2010 | PMID: 20711175 |
Polyamine-dependent production of lymphocytotoxic levels of ammonia by human peripheral blood monocytes. | Flescher E | Immunology letters | 1991 | PMID: 2071175 |
Text-mined citations for rs886041398 ...
HelpRecord last updated Mar 17, 2024
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.