ClinVar Genomic variation as it relates to human health
NM_000334.4(SCN4A):c.3877G>A (p.Val1293Ile)
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.3877G>A (p.Val1293Ile)
Variation ID: 5909 Accession: VCV000005909.38
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q23.3 17: 63944708 (GRCh38) [ NCBI UCSC ] 17: 62022068 (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 Apr 15, 2024 Dec 31, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000334.4:c.3877G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000325.4:p.Val1293Ile missense NC_000017.11:g.63944708C>T NC_000017.10:g.62022068C>T NG_011699.1:g.33211G>A NG_042788.1:g.27616C>T P35499:p.Val1293Ile - Protein change
- V1293I
- Other names
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- Canonical SPDI
- NC_000017.11:63944707: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.
The Genome Aggregation Database (gnomAD) 0.00001
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
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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GH-LCR | - | - | - | GRCh38 | - | 1602 |
SCN4A | - | - |
GRCh38 GRCh37 |
723 | 2015 |
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. |
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Pathogenic (1) |
no assertion criteria provided
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Oct 23, 1995 | RCV000006272.9 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Sep 5, 2023 | RCV000396578.33 | |
not provided (1) |
no classification provided
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- | RCV000509130.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 31, 2023 | RCV000654659.11 |
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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Pathogenic
(Jan 05, 2022)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV002520067.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
Comment:
PP1, PP3, PM2, PS3, PS4_moderate
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Pathogenic
(May 08, 2023)
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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: SCV000615090.3
First in ClinVar: Dec 06, 2016 Last updated: Jan 26, 2024 |
Comment:
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with paramyotonia … (more)
The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with paramyotonia congenita. This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9660885, 30611854) (less)
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Pathogenic
(Sep 05, 2023)
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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: SCV002019134.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 31, 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: SCV000776556.8
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1293 of the SCN4A protein (p.Val1293Ile). … (more)
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1293 of the SCN4A protein (p.Val1293Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant paramyotonia congenita and myotonia congenita (PMID: 8580427, 23771340, 24939454, 27486940). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5909). 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: 9660885, 11744749). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 01, 2023)
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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: SCV001500142.17
First in ClinVar: Mar 14, 2021 Last updated: Apr 15, 2024 |
Comment:
SCN4A: PP1:Strong, PM1, PM2, PS4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 4
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Pathogenic
(Jan 05, 2023)
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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: SCV000329511.8
First in ClinVar: Dec 06, 2016 Last updated: Jan 21, 2023 |
Comment:
Reported previously in patients with mild to moderate myotonia and diagnoses of sodium channel myotonia and paramyotonia congenita with onset in the third decade; however, … (more)
Reported previously in patients with mild to moderate myotonia and diagnoses of sodium channel myotonia and paramyotonia congenita with onset in the third decade; however, no further clinical or segregation information was provided (Farinato et al., 2019); Published functional studies indicate V1293I alters the voltage-dependent gating behavior of SCN4A (Green et al., 1998; Farinato et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16193245, 29606556, 24939454, 28877545, 21221019, 16786525, 27486940, 28325641, 28662944, 32849172, 32660787, 8580427, 9660885, 30611854, 33263785, 11744749, 23771340, 24136861, 21387378) (less)
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Pathogenic
(Oct 23, 1995)
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no assertion criteria provided
Method: literature only
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PARAMYOTONIA CONGENITA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026454.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 17, 2023 |
Comment on evidence:
In 3 unrelated 3-generation families segregating paramyotonia without cold paralysis (see 168300) as an autosomal dominant trait, Koch et al. (1995) identified a heterozygous c.3877G-A … (more)
In 3 unrelated 3-generation families segregating paramyotonia without cold paralysis (see 168300) as an autosomal dominant trait, Koch et al. (1995) identified a heterozygous c.3877G-A transition in exon 21 of the SCN4A gene, resulting in a val1293-to-ile (V1293I) substitution. The amino acid alteration was not found to be a mild polymorphism in their survey of 200 chromosomes from the German population. The predicted mutation was located at the intracellular phase of segment S6 in domain III of the channel protein. Val1293 is conserved in human, rat, and eel. (less)
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not provided
(-)
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no classification provided
Method: phenotyping only
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SCN4A-related disorder
Affected status: yes
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000606996.1
First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017 |
Comment:
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more)
GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Seizures (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature … (more)
Seizures (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the limbs (present) , EMG abnormality (present) , Abnormality of muscle morphology (present) , Abnormality of muscle physiology (present) , Abnormality of facial musculature (present) , Abnormality of the intestine (present) , Abnormality of esophagus morphology (present) , Feeding difficulties (present) (less)
Indication for testing: Diagnostic
Age: 60-69 years
Sex: female
Method: Sanger Sequencing
Testing laboratory: GeneDx
Date variant was reported to submitter: 2016-05-05
Testing laboratory interpretation: Pathogenic
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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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Muscle fat replacement and contractility in patients with skeletal muscle sodium channel disorders. | Pedersen JJ | Scientific reports | 2023 | PMID: 36782059 |
Sequence CLCN1 and SCN4A genes in patients with nondystrophic myotonia in Chinese people. | Meng YX | Medicine | 2022 | PMID: 35866763 |
The Clinical, Myopathological, and Genetic Analysis of 20 Patients With Non-dystrophic Myotonia. | Wang Q | Frontiers in neurology | 2022 | PMID: 35350395 |
Next-generation sequencing application to investigate skeletal muscle channelopathies in a large cohort of Italian patients. | Brugnoni R | Neuromuscular disorders : NMD | 2021 | PMID: 33573884 |
Non-dystrophic myotonias: clinical and mutation spectrum of 70 German patients. | Vereb N | Journal of neurology | 2021 | PMID: 33263785 |
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 |
Mutation spectrum and health status in skeletal muscle channelopathies in Japan. | Sasaki R | Neuromuscular disorders : NMD | 2020 | PMID: 32660787 |
Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate. | Farinato A | Pharmacological research | 2019 | PMID: 30611854 |
The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study. | Andersen G | Brain : a journal of neurology | 2017 | PMID: 29050397 |
Skeletal Muscle Channelopathies: Rare Disorders with Common Pediatric Symptoms. | Matthews E | The Journal of pediatrics | 2017 | PMID: 28662944 |
Spectrum of Nondystrophic Skeletal Muscle Channelopathies in Children. | Al-Ghamdi F | Pediatric neurology | 2017 | PMID: 28325641 |
A Large Dominant Myotonia Congenita Family with a V1293I Mutation in SCN4A. | Chung KW | Journal of clinical neurology (Seoul, Korea) | 2016 | PMID: 27486940 |
Focal and abnormally persistent paralysis associated with congenital paramyotonia. | Magot A | BMJ case reports | 2014 | PMID: 24939454 |
Non-dystrophic myotonia: prospective study of objective and patient reported outcomes. | Trivedi JR | Brain : a journal of neurology | 2013 | PMID: 23771340 |
Mexiletine block of disease-associated mutations in S6 segments of the human skeletal muscle Na(+) channel. | Takahashi MP | The Journal of physiology | 2001 | PMID: 11744749 |
Human sodium channel gating defects caused by missense mutations in S6 segments associated with myotonia: S804F and V1293I. | Green DS | The Journal of physiology | 1998 | PMID: 9660885 |
Paramyotonia congenita without paralysis on exposure to cold: a novel mutation in the SCN4A gene (Val1293Ile). | Koch MC | Neuroreport | 1995 | PMID: 8580427 |
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Text-mined citations for rs121908551 ...
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.