NM_000334.4(SCN4A):c.4307T>C (p.Leu1436Pro) AND Familial hyperkalemic periodic paralysis

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 4, 2021
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:: RCV000819512.11

Allele description [Variation Report for NM_000334.4(SCN4A):c.4307T>C (p.Leu1436Pro)]

NM_000334.4(SCN4A):c.4307T>C (p.Leu1436Pro)

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.4307T>C (p.Leu1436Pro)

HGVS:

NC_000017.11:g.63941975A>G
NG_011699.1:g.35944T>C
NG_042788.1:g.24883A>G
NM_000334.4:c.4307T>CMANE SELECT
NP_000325.4:p.Leu1436Pro
NC_000017.10:g.62019335A>G

Protein change:

L1436P

Links:

dbSNP: rs1598405334

NCBI 1000 Genomes Browser:

rs1598405334

Molecular consequence:

NM_000334.4:c.4307T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000960177	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 4, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18166706, 23516313, 26036855, 21664816, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000960177

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 4, 2021)

germline

clinical testing

PubMed (5)
[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

What causes paramyotonia in the United Kingdom? Common and new SCN4A mutations revealed.

Matthews E, Tan SV, Fialho D, Sweeney MG, Sud R, Haworth A, Stanley E, Cea G, Davis MB, Hanna MG.

Neurology. 2008 Jan 1;70(1):50-3. doi: 10.1212/01.wnl.0000287069.21162.94.

PubMed [citation]

PMID:: 18166706

Prevalence study of genetically defined skeletal muscle channelopathies in England.

Horga A, Raja Rayan DL, Matthews E, Sud R, Fialho D, Durran SC, Burge JA, Portaro S, Davis MB, Haworth A, Hanna MG.

Neurology. 2013 Apr 16;80(16):1472-5. doi: 10.1212/WNL.0b013e31828cf8d0. Epub 2013 Mar 20.

PubMed [citation]

PMID:: 23516313
PMCID:: PMC3662361

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000960177.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with autosomal dominant paramyotonia congenita in several families (PMID: 18166706, 23516313, 26036855, 21664816). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 1436 of the SCN4A protein (p.Leu1436Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.

#	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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