ClinVar Genomic variation as it relates to human health
NM_000334.4(SCN4A):c.2015G>A (p.Arg672His)
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.
Pathogenic(6); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000334.4(SCN4A):c.2015G>A (p.Arg672His)
Variation ID: 5912 Accession: VCV000005912.38
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17q23.3 17: 63959269 (GRCh38) [ NCBI UCSC ] 17: 62036629 (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 Apr 4, 2013 May 12, 2024 Mar 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000334.4:c.2015G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000325.4:p.Arg672His missense NC_000017.11:g.63959269C>T NC_000017.10:g.62036629C>T NG_011699.1:g.18650G>A P35499:p.Arg672His - Protein change
- R672H
- Other names
- -
- Canonical SPDI
- NC_000017.11:63959268:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
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 | ||
---|---|---|---|---|---|---|
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. |
|||
SCN4A | - | - |
GRCh38 GRCh37 |
723 | 2016 |
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. |
---|---|---|---|---|
Pathogenic (2) |
no assertion criteria provided
|
Apr 1, 2002 | RCV000006275.17 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Mar 25, 2024 | RCV000206975.20 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 1, 2022 | RCV001532353.27 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 30, 2022 | RCV002490327.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 7, 2023 | RCV003387718.1 |
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
(Sep 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Acetazolamide-responsive myotonia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004099589.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: SCN4A c.2015G>A (p.Arg672His) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four … (more)
Variant summary: SCN4A c.2015G>A (p.Arg672His) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 247856 control chromosomes (gnomAD). c.2015G>A has been reported in the literature in multiple individuals affected with Hypokalaemic periodic paralysis (Jurkat-Rott_2000, Horga_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies reported this variant affects SCN4A protein function (Jurkat-Rott_2000, Struyk_2008, Sokolov_2010). The following publications have been ascertained in the context of this evaluation (PMID: 23516313, 10944223, 20660662, 17591984). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Jan 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002020023.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Uncertain significance
(Mar 25, 2024)
|
criteria provided, single submitter
Method: research
|
Hyperkalemic periodic paralysis
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004805524.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
Pathogenic
(Nov 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747878.15
First in ClinVar: Jul 10, 2021 Last updated: May 12, 2024 |
Comment:
SCN4A: PM1, PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 3
|
|
Pathogenic
(Mar 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
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
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002797590.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Jan 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001825267.3
First in ClinVar: Sep 08, 2021 Last updated: Mar 04, 2023 |
Comment:
Published functional studies show that R672H alters channel inactivation and decreases current density, thus reducing the number of excitable channels during membrane depolarization (Jurkat-Rott et … (more)
Published functional studies show that R672H alters channel inactivation and decreases current density, thus reducing the number of excitable channels during membrane depolarization (Jurkat-Rott et al., 2000; Sokolov et al., 2010); Not observed at a significant frequency in large population cohorts (gnomAD); Reported previously in at least three families with hypokalemic periodic paralysis type 2 (Jurkat-Rott et al., 2000); 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: 18824591, 20660662, 10944223, 26252573, 20301669, 32619119, 23019082, 19225109, 20301512, 25213595, 25024265, 33144682) (less)
|
|
Pathogenic
(Dec 31, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hyperkalemic periodic paralysis
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000776569.7
First in ClinVar: Feb 02, 2016 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 672 of the SCN4A protein (p.Arg672His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 672 of the SCN4A protein (p.Arg672His). This variant is present in population databases (rs80338788, gnomAD 0.005%). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 10944223, 14504341, 15596759, 19225109, 22253645, 23019082, 25213595). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5912). 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: 10944223, 11912116, 18824591). This variant disrupts the p.Arg672 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10944223, 11558801, 11912116, 15482957, 17330043, 18824591, 19225109, 20660662, 25024265, 26252573). 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)
|
|
Pathogenic
(Apr 01, 2002)
|
no assertion criteria provided
Method: literature only
|
HYPOKALEMIC PERIODIC PARALYSIS, TYPE 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000026457.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 17, 2023 |
Comment on evidence:
In affected members of 3 unrelated families (HypoPP29, HypoPP18, and HypoPP105) with hypokalemic periodic paralysis type 2 (HOKPP2; 613345), Jurkat-Rott et al. (2000) identified a … (more)
In affected members of 3 unrelated families (HypoPP29, HypoPP18, and HypoPP105) with hypokalemic periodic paralysis type 2 (HOKPP2; 613345), Jurkat-Rott et al. (2000) identified a heterozygous c.2016G-A transition in exon 12 of the SCN4A gene, resulting in an arg672-to-his (R672H) substitution in the voltage sensor of domain-2. By in vitro studies in HEK293 cells, Kuzmenkin et al. (2002) showed that the R672H mutation caused enhanced fast inactivation of the SCN4A sodium channel. The inactivation defect could be alleviated by decreased pH, which may explain why some patients have relief by some physical exercise. (less)
|
|
Pathogenic
(Apr 12, 2022)
|
no assertion criteria provided
Method: research
|
Hyperkalemic periodic paralysis
Affected status: yes
Allele origin:
germline
|
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences
Accession: SCV002600054.1
First in ClinVar: Nov 13, 2022 Last updated: Nov 13, 2022 |
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Hyperkalemic periodic paralysis
Affected status: yes
Allele origin:
germline
|
GeneReviews
Accession: SCV000262566.2
First in ClinVar: Feb 02, 2016 Last updated: Oct 01, 2022 |
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Hypokalemic periodic paralysis, type 2
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000040618.3
First in ClinVar: Apr 04, 2013 Last updated: Nov 19, 2022 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Hyperkalemic Periodic Paralysis. | Adam MP | - | 2021 | PMID: 20301669 |
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 |
Muscle edema of the lower limb determined by MRI in Asian hypokalaemic periodic paralysis patients. | Jia BX | Neurological research | 2015 | PMID: 25213595 |
Disrupted coupling of gating charge displacement to Na+ current activation for DIIS4 mutations in hypokalemic periodic paralysis. | Mi W | The Journal of general physiology | 2014 | PMID: 25024265 |
Prevalence study of genetically defined skeletal muscle channelopathies in England. | Horga A | Neurology | 2013 | PMID: 23516313 |
Gender differences in penetrance and phenotype in hypokalemic periodic paralysis. | Ke Q | Muscle & nerve | 2013 | PMID: 23019082 |
Hypokalemic periodic paralysis; two different genes responsible for similar clinical manifestations. | Kim H | Korean journal of pediatrics | 2011 | PMID: 22253645 |
Ion permeation and block of the gating pore in the voltage sensor of NaV1.4 channels with hypokalemic periodic paralysis mutations. | Sokolov S | The Journal of general physiology | 2010 | PMID: 20660662 |
K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. | Jurkat-Rott K | Proceedings of the National Academy of Sciences of the United States of America | 2009 | PMID: 19225109 |
Gating pore currents in DIIS4 mutations of NaV1.4 associated with periodic paralysis: saturation of ion flux and implications for disease pathogenesis. | Struyk AF | The Journal of general physiology | 2008 | PMID: 18824591 |
A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore. | Struyk AF | The Journal of general physiology | 2007 | PMID: 17591984 |
Gating pore current in an inherited ion channelopathy. | Sokolov S | Nature | 2007 | PMID: 17330043 |
New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis. | Vicart S | Neurology | 2004 | PMID: 15596759 |
Mutation screening in Korean hypokalemic periodic paralysis patients: a novel SCN4A Arg672Cys mutation. | Kim MK | Neuromuscular disorders : NMD | 2004 | PMID: 15482957 |
Lack of association of the potassium channel-associated peptide MiRP2-R83H variant with periodic paralysis. | Sternberg D | Neurology | 2003 | PMID: 14504341 |
Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalaemic periodic paralysis type II. | Kuzmenkin A | Brain : a journal of neurology | 2002 | PMID: 11912116 |
Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. | Bendahhou S | Annals of neurology | 2001 | PMID: 11558801 |
Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current. | Jurkat-Rott K | Proceedings of the National Academy of Sciences of the United States of America | 2000 | PMID: 10944223 |
click to load more click to collapse |
Text-mined citations for rs80338788 ...
HelpRecord last updated Jun 02, 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.