NM_000334.4(SCN4A):c.1874T>C (p.Met625Thr) AND Familial hyperkalemic periodic paralysis

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 20, 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:: RCV001911664.7

Allele description [Variation Report for NM_000334.4(SCN4A):c.1874T>C (p.Met625Thr)]

NM_000334.4(SCN4A):c.1874T>C (p.Met625Thr)

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.1874T>C (p.Met625Thr)

HGVS:

NC_000017.11:g.63959410A>G
NG_011699.1:g.18509T>C
NM_000334.4:c.1874T>CMANE SELECT
NP_000325.4:p.Met625Thr
NC_000017.10:g.62036770A>G

Protein change:

M625T

Links:

dbSNP: rs372436021

NCBI 1000 Genomes Browser:

rs372436021

Molecular consequence:

NM_000334.4:c.1874T>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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REP-associated tyrosine transposase [Opitutus terrae]
REP-associated tyrosine transposase [Opitutus terrae]
gi|1789758688|ref|WP_158305410.1|

Protein
ATP synthase F1 subunit gamma [Opitutus terrae]
ATP synthase F1 subunit gamma [Opitutus terrae]
gi|501342067|ref|WP_012373702.1|

Protein
Gm6570 predicted gene 6570 [Mus musculus]
Gm6570 predicted gene 6570 [Mus musculus]
Gene ID:625281

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002175488	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 20, 2022)	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

SCV002175488

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 20, 2022)

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, SCV002175488.3

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

Description

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. 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. This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 625 of the SCN4A protein (p.Met625Thr).

#	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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