ClinVar Genomic variation as it relates to human health
NM_000334.4(SCN4A):c.3404G>A (p.Arg1135His)
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_000334.4(SCN4A):c.3404G>A (p.Arg1135His)
Variation ID: 143201 Accession: VCV000143201.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q23.3 17: 63947082 (GRCh38) [ NCBI UCSC ] 17: 62024442 (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 24, 2015 Apr 15, 2024 Nov 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000334.4:c.3404G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000325.4:p.Arg1135His missense NC_000017.11:g.63947082C>T NC_000017.10:g.62024442C>T NG_011699.1:g.30837G>A NG_042788.1:g.29990C>T P35499:p.Arg1135His - Protein change
- R1135H
- Other names
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- Canonical SPDI
- NC_000017.11:63947081: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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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GH-LCR | - | - | - | GRCh38 | - | 1602 |
SCN4A | - | - |
GRCh38 GRCh37 |
723 | 2015 |
Conditions - Germline
Condition
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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
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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 (2) |
criteria provided, single submitter
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Dec 1, 2020 | RCV000132737.15 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Mar 18, 2022 | RCV000254971.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 28, 2023 | RCV000797599.14 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 12, 2022 | RCV002305449.8 |
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
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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
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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 05, 2018)
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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: SCV000322223.7
First in ClinVar: Oct 09, 2016 Last updated: Apr 17, 2019 |
Comment:
The R1135H pathogenic variant in the SCN4A gene has been reported previously in the heterozygous state in individuals with hypokalaemic periodic paralysis (Matthews et al., … (more)
The R1135H pathogenic variant in the SCN4A gene has been reported previously in the heterozygous state in individuals with hypokalaemic periodic paralysis (Matthews et al., 2009; Sung et al., 2012; Cheng et al., 2011). Functional studies done on muscle fibers from a patient harboring the R1135H pathogenic variant showed increased depolarization tendency at normal and reduced extracellular potassium compatible with the diagnosis, in addition amplitude and rise time of action potentials were reduced compared with controls (Groome et al., 2014). Expression of R1135H in mammalian cells indicate gating defects that include significantly enhanced entry into inactivation and prolonged recovery (Groome et al., 2014). The R1135H variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1135H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1135H as a pathogenic variant. (less)
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Pathogenic
(Dec 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hypokalemic periodic paralysis, type 2
(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: SCV002764873.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Elevated circulating hepatic transaminase concentration (present) , Abnormal left ventricular function (present) , Lactic acidosis (present) , Episodic metabolic acidosis (present) , Abnormal heart morphology … (more)
Elevated circulating hepatic transaminase concentration (present) , Abnormal left ventricular function (present) , Lactic acidosis (present) , Episodic metabolic acidosis (present) , Abnormal heart morphology (present) (less)
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Pathogenic
(Mar 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001879494.2
First in ClinVar: Sep 19, 2021 Last updated: Dec 31, 2022 |
Comment:
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.3481A>G. This variant … (more)
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as c.3481A>G. This variant has been found in several individuals with hypokalemic periodic paralysis, including de novo cases. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments indicate that this variant interferes with normal sodium channel function (PMID: 24549961). The variant is located in a region that is considered important for protein function and/or structure. (less)
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Pathogenic
(Nov 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hyperkalemic periodic paralysis
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000937164.6
First in ClinVar: Aug 14, 2019 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 1135 of the SCN4A protein (p.Arg1135His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1135 of the SCN4A protein (p.Arg1135His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 19118277, 21841462, 23516313, 24549961). In at least one individual the variant was observed to be de novo. This variant is also known as 3481A_x0005_>G. ClinVar contains an entry for this variant (Variation ID: 143201). 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 SCN4A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 24549961). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249365.20
First in ClinVar: May 09, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 2
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Pathogenic
(Apr 12, 2022)
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no assertion criteria provided
Method: research
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Hypokalemic periodic paralysis, type 1
Affected status: yes
Allele origin:
germline
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Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences
Accession: SCV002600045.1
First in ClinVar: Nov 13, 2022 Last updated: Nov 13, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Hypokalemic periodic paralysis, type 2
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000187698.4
First in ClinVar: Aug 10, 2014 Last updated: Nov 19, 2022 |
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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
HelpTitle | Author | Journal | Year | Link |
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Mutation spectrum and health status in skeletal muscle channelopathies in Japan. | Sasaki R | Neuromuscular disorders : NMD | 2020 | PMID: 32660787 |
In vivo assessment of interictal sarcolemmal membrane properties in hypokalaemic and hyperkalaemic periodic paralysis. | Tan SV | Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology | 2020 | PMID: 32066100 |
Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands. | Stunnenberg BC | Neuromuscular disorders : NMD | 2018 | PMID: 29606556 |
Hypokalemic Periodic Paralysis. | Adam MP | - | 2018 | PMID: 20301512 |
Mutation analysis of CACNA1S and SCN4A in patients with hypokalemic periodic paralysis. | Wang XY | Molecular medicine reports | 2015 | PMID: 26252573 |
NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery. | Groome JR | Brain : a journal of neurology | 2014 | PMID: 24549961 |
Prevalence study of genetically defined skeletal muscle channelopathies in England. | Horga A | Neurology | 2013 | PMID: 23516313 |
Genotype and phenotype analysis of patients with sporadic periodic paralysis. | Sung CC | The American journal of the medical sciences | 2012 | PMID: 21841462 |
Identification and functional characterization of Kir2.6 mutations associated with non-familial hypokalemic periodic paralysis. | Cheng CJ | The Journal of biological chemistry | 2011 | PMID: 21665951 |
Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. | Matthews E | Neurology | 2009 | PMID: 19118277 |
Text-mined citations for rs527236150 ...
HelpRecord last updated May 08, 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.