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NM_000334.4(SCN4A):c.3877G>A (p.Val1293Ile) AND Hyperkalemic periodic paralysis

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 31, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000654659.11

Allele description [Variation Report for NM_000334.4(SCN4A):c.3877G>A (p.Val1293Ile)]

NM_000334.4(SCN4A):c.3877G>A (p.Val1293Ile)

Genes:
GH-LCR:growth hormone locus control region [Gene]
SCN4A:sodium voltage-gated channel alpha subunit 4 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q23.3
Genomic location:
Preferred name:
NM_000334.4(SCN4A):c.3877G>A (p.Val1293Ile)
HGVS:
  • NC_000017.11:g.63944708C>T
  • NG_011699.1:g.33211G>A
  • NG_042788.1:g.27616C>T
  • NM_000334.4:c.3877G>AMANE SELECT
  • NP_000325.4:p.Val1293Ile
  • NC_000017.10:g.62022068C>T
  • P35499:p.Val1293Ile
Protein change:
V1293I; VAL1293ILE
Links:
UniProtKB: P35499#VAR_001566; OMIM: 603967.0013; dbSNP: rs121908551
NCBI 1000 Genomes Browser:
rs121908551
Molecular consequence:
  • NM_000334.4:c.3877G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hyperkalemic periodic paralysis
Synonyms:
Gamstorp episodic adynamy; Adynamia episodica hereditaria with or without myotonia; Familial hyperkalemic periodic paralysis; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008224; MedGen: C0238357; Orphanet: 682; OMIM: 170500; Human Phenotype Ontology: HP:0007215

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000776556Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 31, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Paramyotonia congenita without paralysis on exposure to cold: a novel mutation in the SCN4A gene (Val1293Ile).

Koch MC, Baumbach K, George AL, Ricker K.

Neuroreport. 1995 Oct 23;6(15):2001-4.

PubMed [citation]
PMID:
8580427

Non-dystrophic myotonia: prospective study of objective and patient reported outcomes.

Trivedi JR, Bundy B, Statland J, Salajegheh M, Rayan DR, Venance SL, Wang Y, Fialho D, Matthews E, Cleland J, Gorham N, Herbelin L, Cannon S, Amato A, Griggs RC, Hanna MG, Barohn RJ; CINCH Consortium..

Brain. 2013 Jul;136(Pt 7):2189-200. doi: 10.1093/brain/awt133. Epub 2013 Jun 13.

PubMed [citation]
PMID:
23771340
PMCID:
PMC3692030
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000776556.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024