NM_000334.4(SCN4A):c.568C>T (p.Arg190Trp) AND Hyperkalemic periodic paralysis

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 30, 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:: RCV001223461.10

Allele description [Variation Report for NM_000334.4(SCN4A):c.568C>T (p.Arg190Trp)]

NM_000334.4(SCN4A):c.568C>T (p.Arg190Trp)

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.568C>T (p.Arg190Trp)

HGVS:

NC_000017.11:g.63971765G>A
NG_011699.1:g.6154C>T
NM_000334.4:c.568C>TMANE SELECT
NP_000325.4:p.Arg190Trp
NC_000017.10:g.62049125G>A

Protein change:

R190W

Links:

dbSNP: rs763866848

NCBI 1000 Genomes Browser:

rs763866848

Molecular consequence:

NM_000334.4:c.568C>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001395613	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 30, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25961944, 34011629, 29605429, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001395613

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 30, 2023)

germline

clinical testing

PubMed (4)
[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

Excess of rare, inherited truncating mutations in autism.

Krumm N, Turner TN, Baker C, Vives L, Mohajeri K, Witherspoon K, Raja A, Coe BP, Stessman HA, He ZX, Leal SM, Bernier R, Eichler EE.

Nat Genet. 2015 Jun;47(6):582-8. doi: 10.1038/ng.3303. Epub 2015 May 11.

PubMed [citation]

PMID:: 25961944
PMCID:: PMC4449286

A method to delineate de novo missense variants across pathways prioritizes genes linked to autism.

Koire A, Katsonis P, Kim YW, Buchovecky C, Wilson SJ, Lichtarge O.

Sci Transl Med. 2021 May 19;13(594). doi:pii: eabc1739. 10.1126/scitranslmed.abc1739.

PubMed [citation]

PMID:: 34011629
PMCID:: PMC8916821

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001395613.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 190 of the SCN4A protein (p.Arg190Trp). This variant is present in population databases (rs763866848, gnomAD 0.003%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 25961944, 34011629). ClinVar contains an entry for this variant (Variation ID: 951521). 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. Experimental studies have shown that this missense change does not substantially affect SCN4A function (PMID: 29605429). 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.

#	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: May 12, 2024

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