This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 207 of the SLC12A6 protein (p.Arg207Cys). This variant is present in population databases (rs121908429, gnomAD 0.006%). This missense change has been observed in individual(s) with agenesis of the corpus callosum with peripheral neuropathy (PMID: 16606917). ClinVar contains an entry for this variant (Variation ID: 5331). 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 SLC12A6 protein function. Experimental studies have shown that this missense change affects SLC12A6 function (PMID: 21628467). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_001365088.1(SLC12A6):c.619C>T (p.Arg207Cys)
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.
(7)
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.
Conflicting classifications of pathogenicity
Likely pathogenic(3); Uncertain significance(1)
Likely pathogenic(3); Uncertain significance(1)
7
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001365088.1(SLC12A6):c.619C>T (p.Arg207Cys)
Variation ID: 5331 Accession: VCV000005331.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q14 15: 34257713 (GRCh38) [ NCBI UCSC ] 15: 34549914 (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 Apr 4, 2013 Jan 26, 2024 Sep 1, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001365088.1:c.619C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001352017.1:p.Arg207Cys missense NM_001042494.2:c.442C>T NP_001035959.1:p.Arg148Cys missense NM_001042495.2:c.442C>T NP_001035960.1:p.Arg148Cys missense NM_001042496.2:c.592C>T NP_001035961.1:p.Arg198Cys missense NM_001042497.2:c.574C>T NP_001035962.1:p.Arg192Cys missense NM_005135.2:c.466C>T NP_005126.1:p.Arg156Cys missense NM_133647.2:c.619C>T NP_598408.1:p.Arg207Cys missense NC_000015.10:g.34257713G>A NC_000015.9:g.34549914G>A NG_007951.1:g.85352C>T LRG_270:g.85352C>T LRG_270t1:c.466C>T LRG_270p1:p.Arg156Cys LRG_270t2:c.619C>T LRG_270p2:p.Arg207Cys - Protein change
- R207C, R156C, R192C, R198C, R148C
- Other names
- -
- Canonical SPDI
- NC_000015.10:34257712:G:A
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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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
- 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. |
|||
| LOC129390683 | - | - | - | GRCh38 | - | 39 |
| SLC12A6 | - | - |
GRCh38 GRCh38 GRCh37 |
1453 | 1585 | |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 1, 2023 | RCV000005657.13 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV000790223.2 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Aug 23, 2022 | RCV002512812.2 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Agenesis of the corpus callosum with peripheral neuropathy
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002055407.1
First in ClinVar: Jan 12, 2022 Last updated: Jan 12, 2022 |
|
|
|
Uncertain significance
(Aug 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003442824.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 207 of the SLC12A6 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 207 of the SLC12A6 protein (p.Arg207Cys). This variant is present in population databases (rs121908429, gnomAD 0.006%). This missense change has been observed in individual(s) with agenesis of the corpus callosum with peripheral neuropathy (PMID: 16606917). ClinVar contains an entry for this variant (Variation ID: 5331). 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 SLC12A6 protein function. Experimental studies have shown that this missense change affects SLC12A6 function (PMID: 21628467). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
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Likely pathogenic
(Dec 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Agenesis of the corpus callosum with peripheral neuropathy
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV002540224.1
First in ClinVar: Jul 07, 2022 Last updated: Jul 07, 2022 |
Comment:
The SLC12A6 c.619C>T (p.Arg207Cys) missense variant results in the substitution of arginine at amino acid position 207 with cysteine. This variant has been reported in … (more)
The SLC12A6 c.619C>T (p.Arg207Cys) missense variant results in the substitution of arginine at amino acid position 207 with cysteine. This variant has been reported in a homozygous state in one individual presenting with complete agenesis of the corpus callosum, demyelinating neuropathy, dysmorphism and psychomotor retardation (Uyanik et al. 2006). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000054 in the East Asian population (version 2.1.1). A different missense change at the same position, c.620G>A (p.Arg207His), has been noted in two individuals affected with early-onset progressive sensorimotor neuropathy in a heterozygous state and of de novo origin (Park et al. 2020). The Arg207Cys variant protein when expressed in Xenopus oocytes showed significantly reduced K+ influx compared to wild-type, suggestive of impaired potassium-chloride transport (Salin-Cantegrel et al. 2011; Park et al. 2020). Further, the Arg207Cys protein was mislocalized to the perinucleus instead of the plasma membrane in HeLa and PC12 cells (Salin-Cantegrel et al. 2011). Based on the available evidence, the c.619C>T (p.Arg207Cys) variant is classified as likely pathogenic for agenesis of the corpus callosum with peripheral neuropathy. (less)
|
|
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Likely pathogenic
(Sep 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Agenesis of the corpus callosum with peripheral neuropathy
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201160.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Uncertain significance
(-)
|
no assertion criteria provided
Method: literature only
|
Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium
Accession: SCV000929615.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
|
|
|
Pathogenic
(Feb 08, 2022)
|
no assertion criteria provided
Method: clinical testing
|
Agenesis of the corpus callosum with peripheral neuropathy
Affected status: yes
Allele origin:
unknown
|
Center for Molecular Medicine, Children’s Hospital of Fudan University
Accession: SCV002073925.1
First in ClinVar: Feb 09, 2022 Last updated: Feb 09, 2022 |
Sex: male
|
|
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Pathogenic
(Aug 12, 2011)
|
no assertion criteria provided
Method: literature only
|
AGENESIS OF THE CORPUS CALLOSUM WITH PERIPHERAL NEUROPATHY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000025839.2
First in ClinVar: Apr 04, 2013 Last updated: Jan 26, 2024 |
Comment on evidence:
In a 10.5-year-old Turkish boy with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), born of consanguineous parents, Uyanik et al. (2006) identified … (more)
In a 10.5-year-old Turkish boy with agenesis of the corpus callosum with peripheral neuropathy (ACCPN; 218000), born of consanguineous parents, Uyanik et al. (2006) identified a homozygous c.619C-T transition in the SLC12A6 gene, resulting in an arg207-to-cys (R207C) substitution. This patient had slightly less severe neuropathy and also had white matter abnormalities not previously reported in this disorder. The authors noted that this was the first SLC12A6 missense mutation associated with ACCPN and postulated that a dysfunctional SLC12A6 protein may lead to a different phenotype. Variant Function By in vitro studies in mammalian cells, Salin-Cantegrel et al. (2011) demonstrated that the R207C mutant protein interacted with brain-type creatine kinase (CKB; 123280), but had decreased transport activity when expressed in Xenopus oocytes. The mutant protein showed strong localization to the perinuclear region and endoplasmic reticulum, as well as poor membrane localization when expressed in HeLa cells, suggesting a trafficking defect. Western blot analysis showed that the mutant R207C protein also formed stable homodimers, which may have affected transit to the plasma membrane. Treatment with curcumin partially corrected the mislocalization. (less)
|
Comment:
Comment:
The SLC12A6 c.619C>T (p.Arg207Cys) missense variant results in the substitution of arginine at amino acid position 207 with cysteine. This variant has been reported in a homozygous state in one individual presenting with complete agenesis of the corpus callosum, demyelinating neuropathy, dysmorphism and psychomotor retardation (Uyanik et al. 2006). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000054 in the East Asian population (version 2.1.1). A different missense change at the same position, c.620G>A (p.Arg207His), has been noted in two individuals affected with early-onset progressive sensorimotor neuropathy in a heterozygous state and of de novo origin (Park et al. 2020). The Arg207Cys variant protein when expressed in Xenopus oocytes showed significantly reduced K+ influx compared to wild-type, suggestive of impaired potassium-chloride transport (Salin-Cantegrel et al. 2011; Park et al. 2020). Further, the Arg207Cys protein was mislocalized to the perinucleus instead of the plasma membrane in HeLa and PC12 cells (Salin-Cantegrel et al. 2011). Based on the available evidence, the c.619C>T (p.Arg207Cys) variant is classified as likely pathogenic for agenesis of the corpus callosum with peripheral neuropathy.
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:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 207 of the SLC12A6 protein (p.Arg207Cys). This variant is present in population databases (rs121908429, gnomAD 0.006%). This missense change has been observed in individual(s) with agenesis of the corpus callosum with peripheral neuropathy (PMID: 16606917). ClinVar contains an entry for this variant (Variation ID: 5331). 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 SLC12A6 protein function. Experimental studies have shown that this missense change affects SLC12A6 function (PMID: 21628467). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
The SLC12A6 c.619C>T (p.Arg207Cys) missense variant results in the substitution of arginine at amino acid position 207 with cysteine. This variant has been reported in a homozygous state in one individual presenting with complete agenesis of the corpus callosum, demyelinating neuropathy, dysmorphism and psychomotor retardation (Uyanik et al. 2006). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000054 in the East Asian population (version 2.1.1). A different missense change at the same position, c.620G>A (p.Arg207His), has been noted in two individuals affected with early-onset progressive sensorimotor neuropathy in a heterozygous state and of de novo origin (Park et al. 2020). The Arg207Cys variant protein when expressed in Xenopus oocytes showed significantly reduced K+ influx compared to wild-type, suggestive of impaired potassium-chloride transport (Salin-Cantegrel et al. 2011; Park et al. 2020). Further, the Arg207Cys protein was mislocalized to the perinucleus instead of the plasma membrane in HeLa and PC12 cells (Salin-Cantegrel et al. 2011). Based on the available evidence, the c.619C>T (p.Arg207Cys) variant is classified as likely pathogenic for agenesis of the corpus callosum with peripheral neuropathy.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy. | Park J | Journal of medical genetics | 2020 | PMID: 31439721 |
| Transit defect of potassium-chloride Co-transporter 3 is a major pathogenic mechanism in hereditary motor and sensory neuropathy with agenesis of the corpus callosum. | Salin-Cantegrel A | The Journal of biological chemistry | 2011 | PMID: 21628467 |
| Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome. | Uyanik G | Neurology | 2006 | PMID: 16606917 |
| Interaction of RuCl2 (dimethylsulphoxide)4 isomers with DNA. | Loseto F | Anticancer research | 1991 | PMID: 1660691 |
Text-mined citations for rs121908429 ...
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 27, 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.