ClinVar Genomic variation as it relates to human health
NM_172362.3(KCNH1):c.1486G>A (p.Gly496Arg)
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_172362.3(KCNH1):c.1486G>A (p.Gly496Arg)
Variation ID: 183418 Accession: VCV000183418.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q32.2 1: 210804143 (GRCh38) [ NCBI UCSC ] 1: 210977485 (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 Aug 12, 2015 Apr 15, 2024 May 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_172362.3:c.1486G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_758872.1:p.Gly496Arg missense NM_002238.4:c.1405G>A NP_002229.1:p.Gly469Arg missense NC_000001.11:g.210804143C>T NC_000001.10:g.210977485C>T NG_029777.2:g.334973G>A - Protein change
- G469R, G496R
- Other names
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- Canonical SPDI
- NC_000001.11:210804142:C:T
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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
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. |
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KCNH1 | No evidence available | No evidence available |
GRCh38 GRCh37 |
702 | 726 |
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Jan 6, 2022 | RCV000190321.9 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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May 16, 2023 | RCV000498687.5 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Nov 9, 2016 | RCV000623955.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 26, 2021 | RCV001420320.1 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 17, 2023 | RCV002464134.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 27, 2022 | RCV002498803.1 |
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. |
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Pathogenic
(Nov 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Zimmermann-Laband syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680267.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: male
Tissue: blood
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Pathogenic
(Nov 29, 2022)
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criteria provided, single submitter
Method: research
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Temple-Baraitser syndrome
Affected status: yes
Allele origin:
germline
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Laboratory of Medical Genetics, University of Torino
Study: NeuroWES
Accession: SCV002760110.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
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Pathogenic
(Apr 27, 2022)
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criteria provided, single submitter
Method: clinical testing
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Zimmermann-Laband syndrome 1
Temple-Baraitser syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002807597.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Nov 09, 2016)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: yes
Allele origin:
germline
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Ambry Genetics
Accession: SCV000741941.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Macrocephalus (present) , Tall stature (present) , Seizures (present) , Muscular hypotonia (present) , Neurodevelopmental delay (present) , Mongolian blue spot (present) , Generalized tonic-clonic … (more)
Macrocephalus (present) , Tall stature (present) , Seizures (present) , Muscular hypotonia (present) , Neurodevelopmental delay (present) , Mongolian blue spot (present) , Generalized tonic-clonic seizures (present) , Overgrowth (present) , Gastroesophageal reflux (present) , Constipation (present) , Abnormality of the sclera (present) , Mandibular prognathia (present) , Prominent fingertip pads (present) , Overlapping toe (present) , Toe clinodactyly (present) , Notched primary central incisor (present) (less)
Sex: male
Ethnicity/Population group: Native American
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Pathogenic
(Aug 31, 2021)
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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: SCV000589774.4
First in ClinVar: Aug 20, 2017 Last updated: Mar 04, 2023 |
Comment:
Functional studies demonstrate that the G496R variant results in a gain of function effect (Kortum et al., 2015); Not observed in large population cohorts (Lek … (more)
Functional studies demonstrate that the G496R variant results in a gain of function effect (Kortum et al., 2015); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26264464, 33594261, 25915598, 26818738, 33811134) (less)
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Pathogenic
(May 16, 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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Invitae
Accession: SCV003524038.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 183418). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the … (more)
ClinVar contains an entry for this variant (Variation ID: 183418). 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. 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 KCNH1 protein function. This variant is also known as NM_002238.3 c.1405G>A, p.Gly469Arg . This missense change has been observed in individual(s) with Zimmermann-Laband syndrome (PMID: 25915598, 33619735). 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 replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 496 of the KCNH1 protein (p.Gly496Arg). (less)
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Pathogenic
(Apr 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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See cases
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Accession: SCV001622740.1
First in ClinVar: May 20, 2021 Last updated: May 20, 2021 |
Comment:
PP5_very strong;PM1_moderate;PM2_supporting;PM6_moderate;PP2_supporting;PP3_supporting
Clinical Features:
Autistic behavior (present) , Seizure (present) , Dyslexia (present) , Alexia (present) , Hypothyroidism (present) , Neurodevelopmental delay (present) , Motor delay (present) , Protruding … (more)
Autistic behavior (present) , Seizure (present) , Dyslexia (present) , Alexia (present) , Hypothyroidism (present) , Neurodevelopmental delay (present) , Motor delay (present) , Protruding ear (present) (less)
Sex: female
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Pathogenic
(Jan 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Zimmermann-Laband syndrome 1
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002072522.1
First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022 |
Comment:
_x000D_ Criteria applied: PS2, PS3, PS4_MOD, PM2_SUP, PP2, PP3
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Pathogenic
(Jan 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Temple-Baraitser syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003804712.2
First in ClinVar: Mar 04, 2023 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PS4,PS2_MOD,PM5,PM2_SUP,PP2,PP3
Clinical Features:
Pachygyria (present) , Autism (present) , Thin corpus callosum (present) , Global developmental delay (present) , Hypotonia (present) , Self-injurious behavior (present) , Focal-onset seizure … (more)
Pachygyria (present) , Autism (present) , Thin corpus callosum (present) , Global developmental delay (present) , Hypotonia (present) , Self-injurious behavior (present) , Focal-onset seizure (present) (less)
Sex: female
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Pathogenic
(Jun 01, 2015)
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no assertion criteria provided
Method: literature only
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ZIMMERMANN-LABAND SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000238500.2
First in ClinVar: Jul 12, 2015 Last updated: Apr 21, 2017 |
Comment on evidence:
In a 12-year-old Italian girl (patient 4) with Zimmermann-Laband syndrome (ZLS1; 135500), Kortum et al. (2015) identified heterozygosity for a de novo c.1405G-A transition (c.1405G-A, … (more)
In a 12-year-old Italian girl (patient 4) with Zimmermann-Laband syndrome (ZLS1; 135500), Kortum et al. (2015) identified heterozygosity for a de novo c.1405G-A transition (c.1405G-A, NM_002238.3) in the KCNH1 gene, resulting in a gly469-to-arg (G469R) substitution (designation per short transcript/isoform 2) at a highly conserved residue in the S6 segment. The mutation was not found in her unaffected parents or in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Patch-clamp studies in CHO cells demonstrated a dominant action of the G469R mutant over the wildtype channel, with reduced K+ conductance of the heterotetrameric channels at depolarizing potentials but pronounced conductance at negative potentials, consistent with a gain-of-function effect. (less)
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pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Laband syndrome
Affected status: not provided
Allele origin:
de novo,
germline
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Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità
Accession: SCV000212229.1
First in ClinVar: Aug 12, 2015 Last updated: Aug 12, 2015
Comment:
Genomic DNA was isolated from peripheral blood leukocytes, hair bulb and/or buccal cells.
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Comment:
Converted during submission to Pathogenic.
Observation 1: Observation 2: |
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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
HelpText-mined citations for rs730882175 ...
HelpRecord last updated Apr 20, 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.