Published functional studies demonstrate a damaging effect; Xenopus and transfected cells showed that the potassium channel exhibits a higher activity and a higher calcium sensitivity compared with the wild-type channel (Rapetti-Mauss et al., 2015); This variant is associated with the following publications: (PMID: 32641076, 30577886, 26148990, 26198474, 26178367, 28496185, 27443288)
ClinVar Genomic variation as it relates to human health
NM_002250.3(KCNN4):c.1055G>A (p.Arg352His)
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002250.3(KCNN4):c.1055G>A (p.Arg352His)
Variation ID: 252601 Accession: VCV000252601.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.31 19: 43769027 (GRCh38) [ NCBI UCSC ] 19: 44273179 (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 Aug 1, 2016 Oct 20, 2024 Feb 6, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002250.3:c.1055G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002241.1:p.Arg352His missense NC_000019.10:g.43769027C>T NC_000019.9:g.44273179C>T NG_052672.1:g.18113G>A LRG_1305:g.18113G>A LRG_1305t1:c.1055G>A LRG_1305p1:p.Arg352His O15554:p.Arg352His - Protein change
- R352H
- Other names
- -
- Canonical SPDI
- NC_000019.10:43769026:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
Exome Aggregation Consortium (ExAC) 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. |
|||
| KCNN4 | - | - |
GRCh38 GRCh37 |
89 | 102 | |
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
|
Feb 6, 2024 | RCV000239166.28 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 20, 2022 | RCV000412510.9 |
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
(Aug 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001784727.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Published functional studies demonstrate a damaging effect; Xenopus and transfected cells showed that the potassium channel exhibits a higher activity and a higher calcium sensitivity … (more)
Published functional studies demonstrate a damaging effect; Xenopus and transfected cells showed that the potassium channel exhibits a higher activity and a higher calcium sensitivity compared with the wild-type channel (Rapetti-Mauss et al., 2015); This variant is associated with the following publications: (PMID: 32641076, 30577886, 26148990, 26198474, 26178367, 28496185, 27443288) (less)
|
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dehydrated hereditary stomatocytosis 2
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058976.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26148990, PS3_S). In silico tool predictions suggest … (more)
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26148990, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.889, PP3_P). A missense variant is a common mechanism associated with Dehydrated hereditary stomatocytosis 2 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252601, PMID:26148990, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Chronic hemolytic anemia (present) , Hydrops fetalis (present) , Prolonged neonatal jaundice (present)
|
|
|
Pathogenic
(Jun 20, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Dehydrated hereditary stomatocytosis 2
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581315.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4, PM2_SUP, PP2, PP3
|
Number of individuals with the variant: 1
Sex: male
|
|
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Pathogenic
(Oct 30, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
unknown
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000297117.3
First in ClinVar: Aug 01, 2016 Last updated: Dec 24, 2022 |
|
|
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Pathogenic
(Oct 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Dehydrated hereditary stomatocytosis 2
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023216.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Oct 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004298406.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 352 of the KCNN4 protein (p.Arg352His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 352 of the KCNN4 protein (p.Arg352His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with xerocytosis (PMID: 26148990, 26178367, 28496185). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 252601). 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 not expected to disrupt KCNN4 protein function. Experimental studies have shown that this missense change affects KCNN4 function (PMID: 26148990). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Oct 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001501739.23
First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004242966.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
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Pathogenic
(Dec 11, 2015)
|
no assertion criteria provided
Method: literature only
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DEHYDRATED HEREDITARY STOMATOCYTOSIS 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000490257.1
First in ClinVar: Jan 07, 2017 Last updated: Jan 07, 2017 |
Comment on evidence:
In affected members of a 4-generation French family and a 3-generation Polish family with dehydrated hereditary stomatocytosis-2 (DHS2; 616689), Rapetti-Mauss et al. (2015) identified heterozygosity … (more)
In affected members of a 4-generation French family and a 3-generation Polish family with dehydrated hereditary stomatocytosis-2 (DHS2; 616689), Rapetti-Mauss et al. (2015) identified heterozygosity for a c.1055G-A transition in the KCNN4 gene, resulting in an arg352-to-his (R352H) substitution at a highly conserved residue in the calmodulin-interacting region. The mutation was not present in 2 unaffected members of the French family who were tested. Functional analysis in Xenopus oocytes revealed that the current elicited with the mutant channel was higher and sustained longer than that seen with wildtype, but also indicated that the R352H variant is sensitive to the known KCNN4 inhibitor, TRAM34. Transfection studies in HEK293 cells demonstrated higher activity as well as 10-fold higher sensitivity to calcium activation with the mutant channel compared to wildtype. In an Italian mother and son with chronic hemolytic anemia, Andolfo et al. (2015) identified heterozygosity for the R352H mutation in the KCNN4 gene. The mutation segregated with disease in the family and was not found in the 1000 Genomes Project database. (less)
|
Comment:
Comment:
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26148990, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.889, PP3_P). A missense variant is a common mechanism associated with Dehydrated hereditary stomatocytosis 2 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252601, PMID:26148990, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 352 of the KCNN4 protein (p.Arg352His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with xerocytosis (PMID: 26148990, 26178367, 28496185). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 252601). 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 not expected to disrupt KCNN4 protein function. Experimental studies have shown that this missense change affects KCNN4 function (PMID: 26148990). For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
Published functional studies demonstrate a damaging effect; Xenopus and transfected cells showed that the potassium channel exhibits a higher activity and a higher calcium sensitivity compared with the wild-type channel (Rapetti-Mauss et al., 2015); This variant is associated with the following publications: (PMID: 32641076, 30577886, 26148990, 26198474, 26178367, 28496185, 27443288)
Comment:
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:26148990, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.889, PP3_P). A missense variant is a common mechanism associated with Dehydrated hereditary stomatocytosis 2 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000252601, PMID:26148990, PS1_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 352 of the KCNN4 protein (p.Arg352His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with xerocytosis (PMID: 26148990, 26178367, 28496185). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 252601). 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 not expected to disrupt KCNN4 protein function. Experimental studies have shown that this missense change affects KCNN4 function (PMID: 26148990). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 'Gardos Channelopathy': a variant of hereditary Stomatocytosis with complex molecular regulation. | Fermo E | Scientific reports | 2017 | PMID: 28496185 |
| Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis). | Andolfo I | American journal of hematology | 2015 | PMID: 26178367 |
| A mutation in the Gardos channel is associated with hereditary xerocytosis. | Rapetti-Mauss R | Blood | 2015 | PMID: 26148990 |
Text-mined citations for rs774455945 ...
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 Oct 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.