NM_000334.4(SCN4A):c.4301C>A (p.Ser1434Tyr) AND Familial hyperkalemic periodic paralysis

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 1, 2022
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:: RCV001239764.10

Allele description [Variation Report for NM_000334.4(SCN4A):c.4301C>A (p.Ser1434Tyr)]

NM_000334.4(SCN4A):c.4301C>A (p.Ser1434Tyr)

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.4301C>A (p.Ser1434Tyr)

HGVS:

NC_000017.11:g.63941981G>T
NG_011699.1:g.35938C>A
NG_042788.1:g.24889G>T
NM_000334.4:c.4301C>AMANE SELECT
NP_000325.4:p.Ser1434Tyr
NC_000017.10:g.62019341G>T

Protein change:

S1434Y

Links:

dbSNP: rs1908553663

NCBI 1000 Genomes Browser:

rs1908553663

Molecular consequence:

NM_000334.4:c.4301C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hyperkalemic periodic paralysis
Synonyms:: Hyperkalemic periodic paralysis; Gamstorp episodic adynamy; Gamstorp disease
Identifiers:: MONDO: MONDO:0008224; MedGen: C0238357; Orphanet: 682; OMIM: 170500; Human Phenotype Ontology: HP:0007215

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001412661	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23771340, 29111379, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001412661

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 1, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

A SCN4A mutation causing paramyotonia congenita.

Palma C, Prior C, Gómez-González C, Rodríguez-Antolin C, Martínez-Montero P, Pérez de Ayala L, Pascual SI, Molano Mateos J.

Neuromuscul Disord. 2017 Dec;27(12):1123-1125. doi: 10.1016/j.nmd.2017.09.008. Epub 2017 Sep 25.

PubMed [citation]

PMID:: 29111379

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001412661.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ser1434 amino acid residue in SCN4A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23771340, 29111379; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 965335). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1434 of the SCN4A protein (p.Ser1434Tyr).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 22, 2024

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