ClinVar Genomic variation as it relates to human health
NM_000334.4(SCN4A):c.3917G>A (p.Gly1306Glu)
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.3917G>A (p.Gly1306Glu)
Variation ID: 5920 Accession: VCV000005920.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q23.3 17: 63943846 (GRCh38) [ NCBI UCSC ] 17: 62021206 (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 Oct 2, 2016 May 12, 2024 Nov 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000334.4:c.3917G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000325.4:p.Gly1306Glu missense NM_000334.4:c.[3917G>A] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000017.11:g.63943846C>T NC_000017.10:g.62021206C>T NG_011699.1:g.34073G>A NG_042788.1:g.26754C>T P35499:p.Gly1306Glu - Protein change
- G1306E
- Other names
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- Canonical SPDI
- NC_000017.11:63943845: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 | - | 1604 |
SCN4A | - | - |
GRCh38 GRCh37 |
723 | 2016 |
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 (3) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2022 | RCV000489251.25 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 29, 2023 | RCV000552020.16 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 11, 2006 | RCV001799588.12 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001823093.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 26, 2020 | RCV002225070.10 | |
Pathogenic (1) |
criteria provided, single submitter
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May 3, 2022 | RCV002490328.8 |
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
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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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Potassium-aggravated myotonia
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002072972.1
First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022 |
Comment:
The missense variant p.G1306E in SCN4A (NM_000334.4) has been previously reported in heterozygous state in affected individuals (Singh RR et al; Lion-Francois L).Functional studies suggest … (more)
The missense variant p.G1306E in SCN4A (NM_000334.4) has been previously reported in heterozygous state in affected individuals (Singh RR et al; Lion-Francois L).Functional studies suggest a damaging effect (Groome JR et al). A different missense substitution at this codon (p.Gly1306Ala) has been determined to be pathogenic (Torbergsen T et al). The variant has been submitted to ClinVar as Pathogenic. The p.G1306E variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.G1306E missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 1306 of SCN4A is conserved in all mammalian species. The nucleotide c.3917 in SCN4A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Depressed nasal bridge (present) , Gowers sign (present)
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Pathogenic
(Oct 01, 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: SCV002020021.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jun 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Paramyotonia congenita of Von Eulenburg
Affected status: yes
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503661.2
First in ClinVar: Apr 30, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change is predicted to replace glycine with glutamic acid at codon 1306 of the SCN4A protein (p.(Gly1306Glu)). The glycine residue is very highly … (more)
This sequence change is predicted to replace glycine with glutamic acid at codon 1306 of the SCN4A protein (p.(Gly1306Glu)). The glycine residue is very highly conserved (100 vertebrates, UCSC), and is in the cytoplasmic ion transporter region, with a critical role in sodium channel inactivation (PM1, refer to OMIM #603967). There is a moderate physicochemical difference between glycine and glutamic acid. The variant is absent in a large population cohort (PM2, gnomAD v2.1.1 and v3). This variant has been previously reported in over 25 probands with myotonia (PS4, PMID 8308722, 23958773, 20713951, 16832098, 29774303, 25311598, 20076800, 29606556) and segregates with phenotype (PP1, PMID 16832098, 29774303). It has been reported as a de novo change in at least 12 families (PM6_VeryStrong, PMID 23958773, 20713951, 29774303). Functional studies support pathogenicity of the variant (PS3_Supporting, PMID 16392038, 30611854). Muscle biopsy studies demonstrate that p.(Gly1306Glu) affects electrophysiology (PMID 8308722). Multiple lines of computational evidence have conflicting predictions for the missense substitution. A different amino acid change at the same residue has been reported in three families with myotonia fluctuans (PMID 7980103). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant has been classified as PATHOGENIC. The following criteria have been applied: PM6_VeryStrong, PS4, PM1, PM2, PP1, PS3_Supporting. (less)
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Pathogenic
(Mar 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002498322.13
First in ClinVar: Apr 11, 2022 Last updated: May 12, 2024 |
Comment:
SCN4A: PS4, PM2, PM5, PS3:Moderate, PP3, PP4
Number of individuals with the variant: 1
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Pathogenic
(May 03, 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: SCV002782206.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 13, 2021)
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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: SCV000576821.5
First in ClinVar: May 22, 2017 Last updated: Mar 04, 2023 |
Comment:
Observed in multiple unrelated individuals with myotonia in the published literature (Furby et al. 2014; Lion-Francois et al., 2010; Singh et al., 2014); Published functional … (more)
Observed in multiple unrelated individuals with myotonia in the published literature (Furby et al. 2014; Lion-Francois et al., 2010; Singh et al., 2014); Published functional studies demonstrate a damaging effect as electrophysiological studies showed that G1306E reduced fast inactivation of the channel, as well as delayed channel opening and activation (Lerche et al., 1993; Mitrovic et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Different missense changes at this residue (G1306V) and (G1306A) have been reported in the Human Gene Mutation Database and in the published literature (HGMD; Lerche et al., 1993; Ricker et al., 1994; Lion-Francois et al., 2010; Lampe et al., 2004; McClatchey et al., 1992); This variant is associated with the following publications: (PMID: 20713951, 8308722, 7473241, 16392038, 18723887, 25311598, 25088311, 30611854, 32849172, 32593548, 33084218, 26080010, 16832098, 26834636, 7980103, 23958773, 22016737, 23052413, 20237798, 28199958, 18166706, 29899727, 11723275, 20590641, 26944947, 20076800, 32010054) (less)
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Pathogenic
(Nov 29, 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: SCV000658570.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1306 of the SCN4A protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1306 of the SCN4A protein (p.Gly1306Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant SCN4A-related conditions (PMID: 8308722, 16832098, 20713951, 25088311, 25311598, 26944947). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 5920). 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 SCN4A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 7473241, 16392038). This variant disrupts the p.Gly1306 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7980103, 8308722, 26080010). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 11, 2006)
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no assertion criteria provided
Method: literature only
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MYOTONIA PERMANENS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026465.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 17, 2023 |
Comment on evidence:
In a woman with severe myotonia permanens (608390), Lerche et al. (1993) identified a heterozygous c.3917G-A transition in the SCN4A gene, resulting in a gly1306-to-glu … (more)
In a woman with severe myotonia permanens (608390), Lerche et al. (1993) identified a heterozygous c.3917G-A transition in the SCN4A gene, resulting in a gly1306-to-glu (G1306E) substitution in the III-IV linker region of the protein. Patch-clamp recordings on patient muscle samples showed slower sodium fast channel inactivation and an increase in late channel opening, resulting in a steady-state inward current, sustained muscle depolarization, and muscle fiber hyperexcitability. Lerche et al. (1993) identified different pathogenic mutations in the same codon (G1306V; 603967.0007 and G1306A; 603967.0012) in other families with similar disorders, indicating that residue 1306 is important for sodium channel inactivation. Colding-Jorgensen et al. (2006) identified a heterozygous G1306E substitution in a father and son with myotonia permanens. The authors noted that the mutation may interfere with the channel voltage sensor. (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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Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate. | Farinato A | Pharmacological research | 2019 | PMID: 30611854 |
Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands. | Stunnenberg BC | Neuromuscular disorders : NMD | 2018 | PMID: 29606556 |
Myotonia permanens with Nav1.4-G1306E displays varied phenotypes during course of life. | Lehmann-Horn F | Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | 2017 | PMID: 29774303 |
Flecainide-Responsive Myotonia Permanens With SNEL Onset: A New Case and Literature Review. | Portaro S | Pediatrics | 2016 | PMID: 26944947 |
Painful cramps and giant myotonic discharges in a family with the Nav1.4-G1306A mutation. | Torbergsen T | Muscle & nerve | 2015 | PMID: 26080010 |
Mutations in SCN4A: a rare but treatable cause of recurrent life-threatening laryngospasm. | Singh RR | Pediatrics | 2014 | PMID: 25311598 |
Heterozygous CLCN1 mutations can modulate phenotype in sodium channel myotonia. | Furby A | Neuromuscular disorders : NMD | 2014 | PMID: 25088311 |
Diagnosis and outcome of SCN4A-related severe neonatal episodic laryngospasm (SNEL): 2 new cases. | Caietta E | Pediatrics | 2013 | PMID: 23958773 |
Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder. | Lion-Francois L | Neurology | 2010 | PMID: 20713951 |
Clinical Diversity of SCN4A-Mutation-Associated Skeletal Muscle Sodium Channelopathy. | Lee SC | Journal of clinical neurology (Seoul, Korea) | 2009 | PMID: 20076800 |
Autosomal dominant monosymptomatic myotonia permanens. | Colding-Jørgensen E | Neurology | 2006 | PMID: 16832098 |
K-aggravated myotonia mutations at residue G1306 differentially alter deactivation gating of human skeletal muscle sodium channels. | Groome JR | Cellular and molecular neurobiology | 2005 | PMID: 16392038 |
Different effects on gating of three myotonia-causing mutations in the inactivation gate of the human muscle sodium channel. | Mitrović N | The Journal of physiology | 1995 | PMID: 7473241 |
Myotonia fluctuans. A third type of muscle sodium channel disease. | Ricker K | Archives of neurology | 1994 | PMID: 7980103 |
Human sodium channel myotonia: slowed channel inactivation due to substitutions for a glycine within the III-IV linker. | Lerche H | The Journal of physiology | 1993 | PMID: 8308722 |
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Text-mined citations for rs80338792 ...
HelpRecord last updated May 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.