This variant has not been previously reported in the literature to our knowledge, but other pathogenic stop-gain changes have been reported in the literature in association with Kabuki syndrome 2 (PMID: 27302555). This variant is not present in the SNP databases. Sequence analysis of the maternal sample was negative for this variant, indicating that the variant likely occurred as a de novo event. Based on the available evidence, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001291415.2(KDM6A):c.493C>T (p.Arg165Ter)
Germline
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.
(6)
Help
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.
Pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001291415.2(KDM6A):c.493C>T (p.Arg165Ter)
Variation ID: 692010 Accession: VCV000692010.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: Xp11.3 X: 45020659 (GRCh38) [ NCBI UCSC ] X: 44879904 (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 Oct 20, 2019 Feb 20, 2024 Feb 23, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001291415.2:c.493C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001278344.1:p.Arg165Ter nonsense NM_001291416.2:c.493C>T NP_001278345.1:p.Arg165Ter nonsense NM_001291417.2:c.493C>T NP_001278346.1:p.Arg165Ter nonsense NM_001291418.2:c.493C>T NP_001278347.1:p.Arg165Ter nonsense NM_001291421.2:c.-190+9640C>T intron variant NM_021140.4:c.493C>T NP_066963.2:p.Arg165Ter nonsense NR_111960.2:n.857C>T non-coding transcript variant NC_000023.11:g.45020659C>T NC_000023.10:g.44879904C>T NG_016260.1:g.152482C>T LRG_616:g.152482C>T LRG_616t1:c.493C>T - Protein change
- R165*
- Other names
- -
- Canonical SPDI
- NC_000023.11:45020658:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
loss_of_function_variant; Sequence Ontology [ SO:0002054]
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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. |
|||
| KDM6A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
976 | 1174 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2023 | RCV000853276.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 19, 2022 | RCV002269324.2 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV003332269.1 |
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. |
More information
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
(Feb 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
KABUKI SYNDROME 2
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV000996109.1
First in ClinVar: Oct 20, 2019 Last updated: Oct 20, 2019 |
Comment:
This variant has not been previously reported in the literature to our knowledge, but other pathogenic stop-gain changes have been reported in the literature in … (more)
This variant has not been previously reported in the literature to our knowledge, but other pathogenic stop-gain changes have been reported in the literature in association with Kabuki syndrome 2 (PMID: 27302555). This variant is not present in the SNP databases. Sequence analysis of the maternal sample was negative for this variant, indicating that the variant likely occurred as a de novo event. Based on the available evidence, this variant is classified as pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Aug 24, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Kabuki syndrome 2
(X-linked dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Breda Genetics srl
Accession: SCV001443677.1
First in ClinVar: Nov 21, 2020 Last updated: Nov 21, 2020 |
Comment:
The variant c.493C>T (p.Arg165*) in the KDM6A gene is reported as pathogenic for Kabuki syndrome 2 in ClinVar (Variation ID: 692010). The variant creates a … (more)
The variant c.493C>T (p.Arg165*) in the KDM6A gene is reported as pathogenic for Kabuki syndrome 2 in ClinVar (Variation ID: 692010). The variant creates a premature stop codon at amino acid position Arg165, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). There is no information on frequency in gnomAD, 1000 Genomes or NHLI Exome Sequencing Project (ESP). The pathogenic variant c.493C>T (p.Arg165*) has already been reported by Gole et al. (2016) in a 5 years old girl diagnosed with Kabuki syndrome 2 and persistent hyperinsulinism (PMID: 27777708). (less)
|
|
|
Pathogenic
(Aug 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Kabuki syndrome 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001220111.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This premature translational stop signal has been observed in individual(s) with Kabuki syndrome (PMID: 27777708). In at least one individual the variant was observed to … (more)
This premature translational stop signal has been observed in individual(s) with Kabuki syndrome (PMID: 27777708). 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.Arg165*) in the KDM6A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KDM6A are known to be pathogenic (PMID: 23076834, 23913813). ClinVar contains an entry for this variant (Variation ID: 692010). 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 disrupt the consensus splice site. (less)
|
|
|
Pathogenic
(Jan 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002552705.2
First in ClinVar: Jul 29, 2022 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27777708) (less)
|
|
|
Pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Kabuki syndrome 2
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841770.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000692010). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hypopituitarism (present) , Abnormal facial shape (present) , Strabismus (present) , Congenital horizontal nystagmus (present) , Abnormality of the hand (present) , Abnormal nasal tip … (more)
Hypopituitarism (present) , Abnormal facial shape (present) , Strabismus (present) , Congenital horizontal nystagmus (present) , Abnormality of the hand (present) , Abnormal nasal tip morphology (present) , Abnormality of the orbital region (present) , Posteriorly rotated ears (present) , Anterior pituitary hypoplasia (present) , Ventriculomegaly (present) , Intellectual disability (present) (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Malignant tumor of urinary bladder
Affected status: yes
Allele origin:
somatic
|
Laboratory of Urology, Hospital Clinic de Barcelona
Accession: SCV004040478.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
|
Comment:
Comment:
The variant c.493C>T (p.Arg165*) in the KDM6A gene is reported as pathogenic for Kabuki syndrome 2 in ClinVar (Variation ID: 692010). The variant creates a premature stop codon at amino acid position Arg165, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). There is no information on frequency in gnomAD, 1000 Genomes or NHLI Exome Sequencing Project (ESP). The pathogenic variant c.493C>T (p.Arg165*) has already been reported by Gole et al. (2016) in a 5 years old girl diagnosed with Kabuki syndrome 2 and persistent hyperinsulinism (PMID: 27777708).
Comment:
This premature translational stop signal has been observed in individual(s) with Kabuki syndrome (PMID: 27777708). 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.Arg165*) in the KDM6A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KDM6A are known to be pathogenic (PMID: 23076834, 23913813). ClinVar contains an entry for this variant (Variation ID: 692010). 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 disrupt the consensus splice site.
Comment:
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27777708)
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000692010). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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. |
More information
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
loss_of_function_variant
|
Breda Genetics srl
Accession: SCV001443677.1
|
|
Comment:
This variant has not been previously reported in the literature to our knowledge, but other pathogenic stop-gain changes have been reported in the literature in association with Kabuki syndrome 2 (PMID: 27302555). This variant is not present in the SNP databases. Sequence analysis of the maternal sample was negative for this variant, indicating that the variant likely occurred as a de novo event. Based on the available evidence, this variant is classified as pathogenic.
Comment:
The variant c.493C>T (p.Arg165*) in the KDM6A gene is reported as pathogenic for Kabuki syndrome 2 in ClinVar (Variation ID: 692010). The variant creates a premature stop codon at amino acid position Arg165, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). There is no information on frequency in gnomAD, 1000 Genomes or NHLI Exome Sequencing Project (ESP). The pathogenic variant c.493C>T (p.Arg165*) has already been reported by Gole et al. (2016) in a 5 years old girl diagnosed with Kabuki syndrome 2 and persistent hyperinsulinism (PMID: 27777708).
Comment:
This premature translational stop signal has been observed in individual(s) with Kabuki syndrome (PMID: 27777708). 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.Arg165*) in the KDM6A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KDM6A are known to be pathogenic (PMID: 23076834, 23913813). ClinVar contains an entry for this variant (Variation ID: 692010). 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 disrupt the consensus splice site.
Comment:
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27777708)
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000692010). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Persistent Hyperinsulinism in Kabuki Syndrome 2: Case Report and Literature Review. | Gole H | Clinics and practice | 2016 | PMID: 27777708 |
| MLL2 and KDM6A mutations in patients with Kabuki syndrome. | Miyake N | American journal of medical genetics. Part A | 2013 | PMID: 23913813 |
| KDM6A point mutations cause Kabuki syndrome. | Miyake N | Human mutation | 2013 | PMID: 23076834 |
Text-mined citations for rs912069418 ...
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 Sep 29, 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.