VCV000005899.46 - ClinVar

NM_000334.4(SCN4A):c.4343G>A (p.Arg1448His)

Germline

Classification

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.

(14)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000334.4(SCN4A):c.4343G>A (p.Arg1448His)

Variation ID: 5899 Accession: VCV000005899.46

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q23.3 17: 63941939 (GRCh38) [ NCBI UCSC ] 17: 62019299 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 15, 2015	Jan 19, 2025	Jun 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000334.4:c.4343G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000325.4:p.Arg1448His	missense
NC_000017.11:g.63941939C>T
NC_000017.10:g.62019299C>T
NG_011699.1:g.35980G>A
NG_042788.1:g.24847C>T
	P35499:p.Arg1448His

... more HGVS ... less HGVS

Protein change

R1448H

Other names

Canonical SPDI

NC_000017.11:63941938:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

ClinGen: CA117836 UniProtKB: P35499#VAR_001573 OMIM: 603967.0004 dbSNP: rs121908545 VarSome

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
Gene	OMIM	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.
GH-LCR	-	-	-	GRCh38	-	1705
SCN4A		-	-	GRCh38 GRCh37	781	2163

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.
Paramyotonia congenita of Von Eulenburg	Pathogenic (1)	no assertion criteria provided	Jun 1, 1994	RCV000006259.16
Hyperkalemic periodic paralysis	Pathogenic (2)	criteria provided, single submitter	Dec 20, 2023	RCV000206992.17
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 4, 2024	RCV000517055.37
Rhabdomyolysis	Likely pathogenic (1)	no assertion criteria provided	Aug 5, 2017	RCV000662289.9
Delayed gross motor development	Pathogenic (1)	criteria provided, single submitter	Nov 11, 2020	RCV001775065.9
SCN4A-related non-dystrophic myotonia	Pathogenic (1)	no assertion criteria provided	Apr 6, 2022	RCV002267600.8
Potassium-aggravated myotonia	Pathogenic (1)	criteria provided, single submitter	Sep 30, 2021	RCV002288469.9
Congenital myasthenic syndrome 16 Hyperkalemic periodic paralysis Hypokalemic periodic paralysis, type 2 Paramyotonia congenita of Von Eulenburg Potassium-aggravated myotonia	not provided (1)	no classification provided	-	RCV003483425.1
SCN4A-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 16, 2024	RCV004734499.1

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 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.
Pathogenic (Nov 11, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Delayed gross motor development Affected status: yes Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV002012463.1 First in ClinVar: Nov 13, 2021 Last updated: Nov 13, 2021
Pathogenic (Sep 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Potassium-aggravated myotonia Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579415.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PM5, PP1_MOD, PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: male
Pathogenic (Nov 15, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002028045.2 First in ClinVar: Nov 29, 2021 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate that R1448H impacts channel inactivation in vitro (Yang et al., 1994; Mohammadi et al., 2003); Not observed at significant frequency in … (more) Published functional studies demonstrate that R1448H impacts channel inactivation in vitro (Yang et al., 1994; Mohammadi et al., 2003); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7809121, 22507243, 24843232, 8110459, 16624558, 8005599, 32849172, 28779239, 30931713, 30945278, 32594687, 32660787, 1316765, 27415035, 18337730, 32670189, 18166706, 12562902, 1660029) (less)
Pathogenic (Jun 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020017.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 20, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hyperkalemic periodic paralysis Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000776544.6 First in ClinVar: Feb 02, 2016 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 1316765‚ 8005599‚ 18166706‚ 18337730‚ 27415035‚ 7809121‚ 8110459‚ 12562902 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1448 of the SCN4A protein (p.Arg1448His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1448 of the SCN4A protein (p.Arg1448His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant paramyotonia congenita (PMID: 1316765, 8005599, 18166706, 18337730, 27415035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5899). 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: 7809121, 8110459, 12562902). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198147.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Aug 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248152.27 First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024	Comment: SCN4A: PM1, PM2, PM5, PS4:Moderate, PP3, PP4, PS3:Supporting Number of individuals with the variant: 5
pathogenic (Jun 04, 2024)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000615099.2 First in ClinVar: Dec 19, 2017 Last updated: Jan 19, 2025	Publications: PubMed (19) PubMed: 12562902‚ 1316765‚ 18166706‚ 22507243‚ 7676326‚ 7809121‚ 8005599‚ 8110459‚ 28779239‚ 27415035‚ 18337730‚ 30931713‚ 30945278‚ 32849172‚ 32670189‚ 32660787‚ 32594687‚ 35907044‚ 33430134 Comment: This variant has been identified in multiple unrelated individuals with paramyotonia congenita with and without periodic paralysis and segregates with disease in families. This variant … (more) This variant has been identified in multiple unrelated individuals with paramyotonia congenita with and without periodic paralysis and segregates with disease in families. This variant has not been reported in large, multi-ethnic general populations. ((Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8110459, 12562902, 33430134) The variant is located in a region that is considered important for protein function and/or structure. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. (less)
Pathogenic (Jun 01, 1994)	no assertion criteria provided Method: literature only	PARAMYOTONIA CONGENITA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000026441.5 First in ClinVar: Apr 04, 2013 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 1316765‚ 8005599 Comment on evidence: In 2 families with paramyotonia congenita (PMC; 168300), Ptacek et al. (1992) found a heterozygous mutation in the SCN4A gene, resulting in an arg1448-to-his (R1448H) … (more) In 2 families with paramyotonia congenita (PMC; 168300), Ptacek et al. (1992) found a heterozygous mutation in the SCN4A gene, resulting in an arg1448-to-his (R1448H) substitution. Meyer-Kleine et al. (1994) found that the R1448H mutation is exceptionally frequent in the Ravensberger Land region of northwest Germany, where it exists on a specific SCN4A microsatellite haplotype, indicating a founder effect within this subpopulation. (less)
Pathogenic (Sep 16, 2024)	no assertion criteria provided Method: clinical testing	SCN4A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005360667.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The SCN4A c.4343G>A variant is predicted to result in the amino acid substitution p.Arg1448His. This variant has been reported in many unrelated individuals with autosomal … (more) The SCN4A c.4343G>A variant is predicted to result in the amino acid substitution p.Arg1448His. This variant has been reported in many unrelated individuals with autosomal dominant paramyotonia congenita and has segregated in families (kindred 1637 in Ptacek et al 1992. PubMed ID: 1316765; Huang et al 2019. PubMed ID: 30931713; Jiao et al 2019. PubMed ID: 30945278; Meyer et al 2020. PubMed ID: 32670189). This variant has also been reported to occur de novo (Jiao Q et al 2019. PubMed ID: 30945278). Functional studies indicate this variant disrupts normal channel inactivation (Yang N et al 1994. PubMed ID: 7809121). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. (less)
Likely pathogenic (Aug 05, 2017)	no assertion criteria provided Method: literature only	Rhabdomyolysis Affected status: yes Allele origin: germline	Yale Center for Mendelian Genomics, Yale University Accession: SCV000784617.1 First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018	Publications: PubMed (1) PubMed: 28779239 Zygosity: Single Heterozygote
Pathogenic (Apr 06, 2022)	no assertion criteria provided Method: research	SCN4A-related non-dystrophic myotonia Affected status: yes Allele origin: germline	Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Accession: SCV002549799.1 First in ClinVar: Jul 23, 2022 Last updated: Jul 23, 2022
not provided (-)	no classification provided Method: literature only	Hyperkalemic periodic paralysis Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000262572.2 First in ClinVar: Feb 02, 2016 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 1316765 BookShelf: NBK1496 BookShelf: NBK1496
not provided (-)	no classification provided Method: phenotyping only	Hypokalemic periodic paralysis, type 2 Hyperkalemic periodic paralysis Paramyotonia congenita of Von Eulenburg Potassium-aggravated myotonia Congenital myasthenic syndrome 16 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV004228782.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: Variant interpreted as Pathogenic and reported on 12-14-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 12-14-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Abnormal intestine morphology (present) , Abnormal muscle physiology (present) Indication for testing: Diagnostic Zygosity: Single Heterozygote Age: 40-49 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2020-12-14 Testing laboratory interpretation: Pathogenic
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Comment:

Published functional studies demonstrate that R1448H impacts channel inactivation in vitro (Yang et al., 1994; Mohammadi et al., 2003); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7809121, 22507243, 24843232, 8110459, 16624558, 8005599, 32849172, 28779239, 30931713, 30945278, 32594687, 32660787, 1316765, 27415035, 18337730, 32670189, 18166706, 12562902, 1660029)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1448 of the SCN4A protein (p.Arg1448His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant paramyotonia congenita (PMID: 1316765, 8005599, 18166706, 18337730, 27415035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5899). 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: 7809121, 8110459, 12562902). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant has been identified in multiple unrelated individuals with paramyotonia congenita with and without periodic paralysis and segregates with disease in families. This variant has not been reported in large, multi-ethnic general populations. ((Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8110459, 12562902, 33430134) The variant is located in a region that is considered important for protein function and/or structure. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease.

Comment:

The SCN4A c.4343G>A variant is predicted to result in the amino acid substitution p.Arg1448His. This variant has been reported in many unrelated individuals with autosomal dominant paramyotonia congenita and has segregated in families (kindred 1637 in Ptacek et al 1992. PubMed ID: 1316765; Huang et al 2019. PubMed ID: 30931713; Jiao et al 2019. PubMed ID: 30945278; Meyer et al 2020. PubMed ID: 32670189). This variant has also been reported to occur de novo (Jiao Q et al 2019. PubMed ID: 30945278). Functional studies indicate this variant disrupts normal channel inactivation (Yang N et al 1994. PubMed ID: 7809121). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 12-14-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic spectrum and founder effect of non-dystrophic myotonia: a Japanese case series study.	Yuan JH	Journal of neurology	2022	PMID: 35907044
Changes in Resurgent Sodium Current Contribute to the Hyperexcitability of Muscles in Patients with Paramyotonia Congenita.	Huang CW	Biomedicines	2021	PMID: 33430134
Hyperkalemic Periodic Paralysis.	Adam MP	-	2021	PMID: 20301669
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
Genotype-Phenotype Correlations and Characterization of Medication Use in Inherited Myotonic Disorders.	Meyer AP	Frontiers in neurology	2020	PMID: 32670189
Mutation spectrum and health status in skeletal muscle channelopathies in Japan.	Sasaki R	Neuromuscular disorders : NMD	2020	PMID: 32660787
[Clinical, myopathological and genetic features of two Chinese families with paramyotonia congenita].	Song J	Zhonghua nei ke za zhi	2020	PMID: 32594687
The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders.	Jiao Q	Clinical genetics	2019	PMID: 30945278
Overlap of periodic paralysis and paramyotonia congenita caused by SCN4A gene mutations two family reports and literature review.	Huang S	Channels (Austin, Tex.)	2019	PMID: 30931713
Exome sequencing in Jewish and Arab patients with rhabdomyolysis reveals single-gene etiology in 43% of cases.	Vivante A	Pediatric nephrology (Berlin, Germany)	2017	PMID: 28779239
Sequence CLCN1 and SCN4A in patients with Nondystrophic myotonias in Chinese populations: Genetic and pedigree analysis of 10 families and review of the literature.	Yang X	Channels (Austin, Tex.)	2017	PMID: 27415035
Paramyotonia congenita: from clinical diagnosis to in silico protein modeling analysis.	Nurputra DK	Pediatrics international : official journal of the Japan Pediatric Society	2012	PMID: 22507243
In tandem analysis of CLCN1 and SCN4A greatly enhances mutation detection in families with non-dystrophic myotonia.	Trip J	European journal of human genetics : EJHG	2008	PMID: 18337730
What causes paramyotonia in the United Kingdom? Common and new SCN4A mutations revealed.	Matthews E	Neurology	2008	PMID: 18166706
Mechanisms of cold sensitivity of paramyotonia congenita mutation R1448H and overlap syndrome mutation M1360V.	Mohammadi B	The Journal of physiology	2003	PMID: 12562902
In vivo sodium channel structure/function studies: consecutive Arg1448 changes to Cys, His, and Pro at the extracellular surface of IVS4.	Wang J	Society of General Physiologists series	1995	PMID: 7676326
Sodium channel mutations in paramyotonia congenita uncouple inactivation from activation.	Chahine M	Neuron	1994	PMID: 8110459
Molecular and genetic characterisation of German families with paramyotonia congenita and demonstration of founder effect in the Ravensberg families.	Meyer-Kleine C	Human genetics	1994	PMID: 8005599
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
Mutations in an S4 segment of the adult skeletal muscle sodium channel cause paramyotonia congenita.	Ptácek LJ	Neuron	1992	PMID: 1316765
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Text-mined citations for rs121908545 ...

These 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 Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_000334.4(SCN4A):c.4343G>A (p.Arg1448His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908545 ...