NM_174934.4(SCN4B):c.298C>T (p.Arg100Cys) AND Long QT syndrome 10

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 18, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000790454.4

Allele description [Variation Report for NM_174934.4(SCN4B):c.298C>T (p.Arg100Cys)]

NM_174934.4(SCN4B):c.298C>T (p.Arg100Cys)

Genes:

LOC126861356:BRD4-independent group 4 enhancer GRCh37_chr11:118014519-118015718 [Gene]
SCN4B:sodium voltage-gated channel beta subunit 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_174934.4(SCN4B):c.298C>T (p.Arg100Cys)

HGVS:

NC_000011.10:g.118143998G>A
NG_011710.1:g.13918C>T
NM_001142348.2:c.62-2662C>T
NM_001142349.2:c.-33C>T
NM_174934.4:c.298C>TMANE SELECT
NP_777594.1:p.Arg100Cys
NP_777594.1:p.Arg100Cys
LRG_330t1:c.298C>T
LRG_330:g.13918C>T
LRG_330p1:p.Arg100Cys
NC_000011.9:g.118014713G>A
NM_174934.3:c.298C>T
NR_024527.2:n.441C>T

Protein change:

R100C

Links:

dbSNP: rs149497652

NCBI 1000 Genomes Browser:

rs149497652

Molecular consequence:

NM_001142349.2:c.-33C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001142348.2:c.62-2662C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_174934.4:c.298C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_024527.2:n.441C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Long QT syndrome 10 (LQT10)
Identifiers:: MONDO: MONDO:0012737; MedGen: C2678484; Orphanet: 101016; Orphanet: 768; OMIM: 611819

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000929781	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 21, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003004635	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 18, 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

SCV000929781

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 21, 2019)

unknown

clinical testing

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

SCV003004635

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 18, 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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues, SCV000929781.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003004635.2

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 100 of the SCN4B protein (p.Arg100Cys). This variant is present in population databases (rs149497652, gnomAD 0.01%). 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. ClinVar contains an entry for this variant (Variation ID: 637988). This variant has not been reported in the literature in individuals affected with SCN4B-related conditions.

#	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: Feb 28, 2024

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