NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr) AND Familial hyperkalemic periodic paralysis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 20, 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:: RCV001217902.11

Allele description [Variation Report for NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr)]

NM_000334.4(SCN4A):c.4364T>C (p.Ile1455Thr)

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.4364T>C (p.Ile1455Thr)

HGVS:

NC_000017.11:g.63941918A>G
NG_011699.1:g.36001T>C
NG_042788.1:g.24826A>G
NM_000334.4:c.4364T>CMANE SELECT
NP_000325.4:p.Ile1455Thr
NC_000017.10:g.62019278A>G

Protein change:

I1455T

Links:

dbSNP: rs377176361

NCBI 1000 Genomes Browser:

rs377176361

Molecular consequence:

NM_000334.4:c.4364T>C - 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

Recent activity

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603300471F1 NCI_CGAP_Mam3 Mus musculus cDNA clone IMAGE:5341240 5', mRNA sequenc...
603300471F1 NCI_CGAP_Mam3 Mus musculus cDNA clone IMAGE:5341240 5', mRNA sequence
gi|15567728|gnl|dbEST|9499805|gb|BI 2.1|

Nucleotide
uncharacterized protein C12orf50 isoform X3 [Homo sapiens]
uncharacterized protein C12orf50 isoform X3 [Homo sapiens]
gi|1034578237|ref|XP_016874376.1|

Protein
RecName: Full=Thioredoxin reductase 3; AltName: Full=Thioredoxin and glutathione...
RecName: Full=Thioredoxin reductase 3; AltName: Full=Thioredoxin and glutathione reductase; AltName: Full=Thioredoxin reductase TR2
gi|510120859|sp|Q86VQ6.4|TRXR3_HUMA

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001389761	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 20, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28024841, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001389761

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 20, 2023)

germline

clinical testing

PubMed (2)
[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

A novel Ile1455Thr variant in the skeletal muscle sodium channel alpha-subunit in a patient with a severe adult-onset proximal myopathy with electrical myotonia and a patient with mild paramyotonia phenotype.

Bednarz M, Stunnenberg BC, Kusters B, Kamsteeg EJ, Saris CG, Groome J, Winston V, Meola G, Jurkat-Rott K, Voermans NC.

Neuromuscul Disord. 2017 Feb;27(2):175-182. doi: 10.1016/j.nmd.2016.09.023. Epub 2016 Oct 19.

PubMed [citation]

PMID:: 28024841

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001389761.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1455 of the SCN4A protein (p.Ile1455Thr). This variant is present in population databases (rs377176361, gnomAD 0.002%). This missense change has been observed in individuals with clinical features of proximal myopathy and paramyotonia congenita (PMID: 28024841). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 932430). 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 80%. Experimental studies have shown that this missense change affects SCN4A function (PMID: 28024841). For these reasons, this variant has been classified as Pathogenic.

#	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: Oct 20, 2024

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