The C555R variant is absent from a large population database, indicating it is a rare variant. The C555R variant is a non-conservative amino acid substitution which may be likely to cause structural deficiencies Multiple in silico analyses predict the C555R variant is probably damaging to the protein structure/function. The C555R variant is localized to the S5 helical transmembrane domain. It is at the same locus as an existing likely pathogenic classified variant, C555Y. The C555R variant was recently published in association with a Long QT Syndrome phenotype in two affected individuals with recurrent syncopal events. Additionally, in vitro functional studies using Western blot, on-cell Westerns, and patch clamp analysis show that C555R results in lower KCNH2 channel protein expression, lack of proper localization to the cell surface, and loss of channel function with a partially dominant-negative effect on co-expressed wildtype channel current (Beidokhti et al., 2021). Therefore, this variant is likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000238.4(KCNH2):c.1663T>C (p.Cys555Arg)
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.
(1)
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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.
Likely pathogenic
1
criteria provided, single submitter
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000238.4(KCNH2):c.1663T>C (p.Cys555Arg)
Variation ID: 3064233 Accession: VCV003064233.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 7q36.1 7: 150951730 (GRCh38) [ NCBI UCSC ] 7: 150648818 (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 Mar 30, 2024 Mar 30, 2024 Mar 15, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000238.4:c.1663T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000229.1:p.Cys555Arg missense NM_001204798.2:c.643T>C NP_001191727.1:p.Cys215Arg missense NM_001406753.1:c.1375T>C NP_001393682.1:p.Cys459Arg missense NM_001406755.1:c.1486T>C NP_001393684.1:p.Cys496Arg missense NM_001406756.1:c.1375T>C NP_001393685.1:p.Cys459Arg missense NM_001406757.1:c.1363T>C NP_001393686.1:p.Cys455Arg missense NM_172056.3:c.1663T>C NP_742053.1:p.Cys555Arg missense NM_172057.3:c.643T>C NP_742054.1:p.Cys215Arg missense NR_176254.1:n.2071T>C non-coding transcript variant NR_176255.1:n.944T>C non-coding transcript variant NC_000007.14:g.150951730A>G NC_000007.13:g.150648818A>G NG_008916.1:g.31197T>C LRG_288:g.31197T>C LRG_288t1:c.1663T>C LRG_288p1:p.Cys555Arg LRG_288t2:c.1663T>C LRG_288p2:p.Cys555Arg LRG_288t3:c.643T>C LRG_288p3:p.Cys215Arg - Protein change
- C215R, C455R, C459R, C496R, C555R
- Other names
- -
- Canonical SPDI
- NC_000007.14:150951729:A:G
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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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loss_of_function_variant; Sequence Ontology [ SO:0002054]
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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
Help
The frequency of the allele represented by this VCV record.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
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| KCNH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3223 | 3309 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (1) |
criteria provided, single submitter
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Mar 15, 2024 | RCV003988816.2 |
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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Likely pathogenic
(Mar 15, 2024)
|
criteria provided, single submitter
Method: research, in vitro
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Long QT syndrome 2
(Autosomal dominant inheritance)
Affected status: yes, not applicable
Allele origin:
germline,
not applicable
|
Pediatric Genomics Discovery Program, Yale University
Accession: SCV004801298.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
The C555R variant is absent from a large population database, indicating it is a rare variant. The C555R variant is a non-conservative amino acid substitution … (more)
The C555R variant is absent from a large population database, indicating it is a rare variant. The C555R variant is a non-conservative amino acid substitution which may be likely to cause structural deficiencies Multiple in silico analyses predict the C555R variant is probably damaging to the protein structure/function. The C555R variant is localized to the S5 helical transmembrane domain. It is at the same locus as an existing likely pathogenic classified variant, C555Y. The C555R variant was recently published in association with a Long QT Syndrome phenotype in two affected individuals with recurrent syncopal events. Additionally, in vitro functional studies using Western blot, on-cell Westerns, and patch clamp analysis show that C555R results in lower KCNH2 channel protein expression, lack of proper localization to the cell surface, and loss of channel function with a partially dominant-negative effect on co-expressed wildtype channel current (Beidokhti et al., 2021). Therefore, this variant is likely pathogenic. (less)
Observation 1:
Number of individuals with the variant: 3
Clinical Features:
Prolonged QT interval (present)
Observation 2:
Result:
Western Blot: Our results indicated that at 48 h post-transfection, KCNH2-WT showed two bands at 135 kD and 155 kD whereas KCNH2-Cys555Arg exhibited a nearly absent mature band at 155 kD (Fig. 2a).
Observation 3:
Result:
On-Cell Western: Our results indicate that KCNH2-Cys555Arg does not result in substantial protein expression on the cell surface. In permeabilized cells both KCNH2-WT and KCNH2-Cys555Arg were detected while in nonpermeabilized cells only KCNH2-WT showed substantial protein expression on the cell surface.
Observation 4:
Result:
Patch Clamp Analysis: Our result showed that cells transfected with KCNQ1-WT/ KCNE1 and KCNQ1-Arg293Cys/KCNE1 had a mean current density of 1695.03 ± 123.51 pA/pF (n = 11) and 2898.21 ± 474.80 pA/pF (n = 7), respectively, which was significant (Fig. 5b). The normalized voltage-dependent activation curves for KCNQ1-WT/ KCNE1 and KCNQ1-Arg293Cys/ KCNE1 showed that there is no significant difference. The V1⁄2 for KCNQ1-WT/ KCNE1 is 19.06 ± 5.86 mV and the V1⁄2 for KCNQ1-Arg293Cys/ KCNE1 is 24.55 ± 5.87 mV (Fig. 5c). These results indicated that the KCNQ1-Arg293Cys variant leads to increased current density, but a preservation of voltage-dependent gating characteristics equivalent to the wild type.
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Comment:
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. |
|---|---|---|---|---|
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loss_of_function_variant
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Pediatric Genomics Discovery Program, Yale University
Accession: SCV004801298.1
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Comment:
The C555R variant is absent from a large population database, indicating it is a rare variant. The C555R variant is a non-conservative amino acid substitution which may be likely to cause structural deficiencies Multiple in silico analyses predict the C555R variant is probably damaging to the protein structure/function. The C555R variant is localized to the S5 helical transmembrane domain. It is at the same locus as an existing likely pathogenic classified variant, C555Y. The C555R variant was recently published in association with a Long QT Syndrome phenotype in two affected individuals with recurrent syncopal events. Additionally, in vitro functional studies using Western blot, on-cell Westerns, and patch clamp analysis show that C555R results in lower KCNH2 channel protein expression, lack of proper localization to the cell surface, and loss of channel function with a partially dominant-negative effect on co-expressed wildtype channel current (Beidokhti et al., 2021). Therefore, this variant is likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional testing for variant prioritization in a family with long QT syndrome. | Najari Beidokhti M | Molecular genetics and genomics : MGG | 2021 | PMID: 33876311 |
Text-mined citations for this variant ...
HelpRecord last updated Jun 23, 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.