ClinVar Genomic variation as it relates to human health
NM_000334.4(SCN4A):c.3466G>A (p.Ala1156Thr)
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.3466G>A (p.Ala1156Thr)
Variation ID: 5900 Accession: VCV000005900.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q23.3 17: 63945614 (GRCh38) [ NCBI UCSC ] 17: 62022974 (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 Feb 13, 2015 May 1, 2024 Dec 10, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000334.4:c.3466G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000325.4:p.Ala1156Thr missense NC_000017.11:g.63945614C>T NC_000017.10:g.62022974C>T NG_011699.1:g.32305G>A NG_042788.1:g.28522C>T P35499:p.Ala1156Thr - Protein change
- A1156T
- Other names
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- Canonical SPDI
- NC_000017.11:63945613: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00003
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 | - | 1594 |
SCN4A | - | - |
GRCh38 GRCh37 |
721 | 2010 |
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 (1) |
no assertion criteria provided
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Oct 1, 1992 | RCV000006260.10 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 10, 2023 | RCV000020271.14 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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May 23, 2022 | RCV000516392.25 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2022 | RCV001004616.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 24, 2022 | RCV002496281.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 8, 2023 | RCV003162214.5 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV003335017.1 |
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
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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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Likely pathogenic
(Jan 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hyperkalemic periodic paralysis
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579821.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4_SUP, PP1, PP3
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Number of individuals with the variant: 1
Sex: male
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Pathogenic
(Aug 23, 2019)
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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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Revvity Omics, Revvity
Accession: SCV002020027.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jul 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249364.20
First in ClinVar: May 12, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Mar 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003862265.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The c.3466G>A (p.A1156T) alteration is located in exon 19 (coding exon 19) of the SCN4A gene. This alteration results from a G to A substitution … (more)
The c.3466G>A (p.A1156T) alteration is located in exon 19 (coding exon 19) of the SCN4A gene. This alteration results from a G to A substitution at nucleotide position 3466, causing the alanine (A) at amino acid position 1156 to be replaced by a threonine (T). _x000D_ _x000D_ The SCN4A c.3466G>A (p.A1156T) alteration is classified as pathogenic for autosomal dominant SCN4A-related myotonia and/or periodic paralysis disorders; however, its clinical significance for autosomal recessive SCN4A-related congenital myasthenic syndrome is unclear. Based on data from gnomAD, the A allele has an overall frequency of 0.005% (15/281704) total alleles studied. The highest observed frequency was 0.044% (11/25072) of European (Finnish) alleles. This alteration has been reported in multiple individuals and families with clinical features consistent with SCN4A-related myotonia and/or periodic paralysis disorders (McClatchey, 1992; Lee, 2009; Song, 2012; Palmio, 2017; Sainio, 2022). EMG myotonic discharges have been detected in multiple individuals with this variant (Palmio, 2017). Another alteration at the same codon, c.3466G>T (p.A1156S), has been described in an individual with sodium-channel myotonia (Maggi, 2020). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.A1156T alteration exhibited a disturbance in channel inactivation compared to the wild-type (Yang, 1994; Palmio, 2017). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Likely pathogenic
(May 10, 2019)
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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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Athena Diagnostics Inc
Accession: SCV000615084.3
First in ClinVar: Dec 19, 2017 Last updated: Jan 18, 2020 |
Comment:
The best available variant frequency is 3-10 times higher than the disease allele frequency, and data include at least 10 observations. Statistically enriched in uncharacterized … (more)
The best available variant frequency is 3-10 times higher than the disease allele frequency, and data include at least 10 observations. Statistically enriched in uncharacterized patients compared to unmatched population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. (less)
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Focal-onset seizure
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
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Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001162774.2
First in ClinVar: Feb 29, 2020 Last updated: Apr 02, 2022 |
Sex: male
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Pathogenic
(Apr 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Paramyotonia congenita of Von Eulenburg
Hypokalemic periodic paralysis, type 1 Hyperkalemic periodic paralysis Potassium-aggravated myotonia Hypokalemic periodic paralysis, type 2 Congenital myasthenic syndrome 16
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002809749.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(May 23, 2022)
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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: SCV002520120.2
First in ClinVar: May 28, 2022 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that this variant results in altered channel inactivation and voltage dependence compared to wild-type controls (Yang et al., 1994; Hayward et … (more)
Published functional studies demonstrate that this variant results in altered channel inactivation and voltage dependence compared to wild-type controls (Yang et al., 1994; Hayward et al., 1999; Palmio et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in nearby residues reported in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 7809121, 22016737, 10227633, 14501839, 22926674, 20076800, 16193245, 1338909, 28330959, 31440732, 32849172, 32619119) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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SCN4A-Related Disorders
Affected status: yes
Allele origin:
germline
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Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046438.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a heterozygous change in patients with paramyotonia congenita, hyperkalaemic periodic paralysis, exercise- and cold-induced muscle cramps, muscle stiffness, … (more)
This variant has been previously reported as a heterozygous change in patients with paramyotonia congenita, hyperkalaemic periodic paralysis, exercise- and cold-induced muscle cramps, muscle stiffness, myalgia, and generalized seizures (PMID: 1338909, 28330959, 22926674, 31440732, 34418069). Different amino acid changes at the same residue (p.Ala1156Ser) have been previously reported in individuals with myotonia and periodic paralyses (PMID: 32849172). Functional studies showed that the c.3466G>A (p.Ala1156Thr) variant resulted in mild attenuation and disturbance of channel inactivation due to reduced macroscopic rate, accelerated recovery, and altered voltage dependence (PMID: 1338909, 7809121, 28330959). The c.3466G>A (p.Ala1156Thr) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (15/281704) and thus is presumed to be rare. The c.3466G>A (p.Ala1156Thr) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.3466G>A (p.Ala1156Thr) variant is classified as Pathogenic. (less)
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Pathogenic
(Dec 10, 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: SCV001206949.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1156 of the SCN4A protein (p.Ala1156Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1156 of the SCN4A protein (p.Ala1156Thr). This variant is present in population databases (rs80338958, gnomAD 0.05%). This missense change has been observed in individuals with autosomal dominant SCN4A-related disease (PMID: 1338909, 28330959). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5900). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN4A protein function. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7809121, 28330959). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Oct 01, 1992)
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no assertion criteria provided
Method: literature only
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PARAMYOTONIA CONGENITA/HYPERKALEMIC PERIODIC PARALYSIS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026442.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 17, 2023 |
Comment on evidence:
In a family of Finnish extraction whose affected members displayed an unusual mixture of clinical features of both paramyotonia congenita (PMC; 168300) and hyperkalemic periodic … (more)
In a family of Finnish extraction whose affected members displayed an unusual mixture of clinical features of both paramyotonia congenita (PMC; 168300) and hyperkalemic periodic paralysis (HYPP; 170500), McClatchey et al. (1992) identified a heterozygous c.3466G-A transition in the SCN4A gene, resulting in an ala1156-to-thr (A1156T) substitution. (less)
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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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Effectiveness of clinical exome sequencing in adult patients with difficult-to-diagnose neurological disorders. | Sainio MT | Acta neurologica Scandinavica | 2022 | PMID: 34418069 |
Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients. | Maggi L | Frontiers in neurology | 2020 | PMID: 32849172 |
Normokalemic periodic paralysis is not a distinct disease. | Song YW | Muscle & nerve | 2012 | PMID: 22926674 |
Clinical Diversity of SCN4A-Mutation-Associated Skeletal Muscle Sodium Channelopathy. | Lee SC | Journal of clinical neurology (Seoul, Korea) | 2009 | PMID: 20076800 |
Gating of myotonic Na channel mutants defines the response to mexiletine and a potent derivative. | Desaphy JF | Neurology | 2001 | PMID: 11723275 |
Sodium channel mutations in paramyotonia congenita exhibit similar biophysical phenotypes in vitro. | Yang N | Proceedings of the National Academy of Sciences of the United States of America | 1994 | PMID: 7809121 |
Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel. | McClatchey AI | Nature genetics | 1992 | PMID: 1338909 |
Text-mined citations for rs80338958 ...
HelpRecord last updated May 01, 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.