NM_000334.4(SCN4A):c.739G>C (p.Val247Leu) AND Familial hyperkalemic periodic paralysis

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 26, 2024
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:: RCV001227346.9

Allele description [Variation Report for NM_000334.4(SCN4A):c.739G>C (p.Val247Leu)]

NM_000334.4(SCN4A):c.739G>C (p.Val247Leu)

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.739G>C (p.Val247Leu)

HGVS:

NC_000017.11:g.63968320C>G
NG_011699.1:g.9599G>C
NM_000334.4:c.739G>CMANE SELECT
NP_000325.4:p.Val247Leu
NC_000017.10:g.62045680C>G

Protein change:

V247L

Links:

dbSNP: rs755321637

NCBI 1000 Genomes Browser:

rs755321637

Molecular consequence:

NM_000334.4:c.739G>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

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PREDICTED: Homo sapiens acyl-CoA synthetase bubblegum family member 2 (ACSBG2), ...
PREDICTED: Homo sapiens acyl-CoA synthetase bubblegum family member 2 (ACSBG2), transcript variant X1, mRNA
gi|2462567924|ref|XM_054322249.1|

Nucleotide
brain my050 protein [Homo sapiens]
brain my050 protein [Homo sapiens]
gi|12002046|gb|AAG43166.1|AF063608_

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001399699	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001399699

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 26, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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, SCV001399699.5

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

Description

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 247 of the SCN4A protein (p.Val247Leu). This variant is present in population databases (rs755321637, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 954819). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN4A protein function. 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: Sep 29, 2024

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