NM_000335.5(SCN5A):c.5589G>T (p.Glu1863Asp) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Oct 10, 2023
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:: RCV000183127.20

Allele description [Variation Report for NM_000335.5(SCN5A):c.5589G>T (p.Glu1863Asp)]

NM_000335.5(SCN5A):c.5589G>T (p.Glu1863Asp)

Gene:

SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000335.5(SCN5A):c.5589G>T (p.Glu1863Asp)

Other names:

p.E1864D:GAG>GAT

HGVS:

NC_000003.12:g.38550780C>A
NG_008934.1:g.103893G>T
NM_000335.5:c.5589G>TMANE SELECT
NM_001099404.2:c.5592G>T
NM_001099405.2:c.5538G>T
NM_001160160.2:c.5493G>T
NM_001160161.2:c.5430G>T
NM_001354701.2:c.5535G>T
NM_198056.3:c.5592G>T
NP_000326.2:p.Glu1863Asp
NP_001092874.1:p.Glu1864Asp
NP_001092875.1:p.Glu1846Asp
NP_001153632.1:p.Glu1831Asp
NP_001153633.1:p.Glu1810Asp
NP_001341630.1:p.Glu1845Asp
NP_932173.1:p.Glu1864Asp
NP_932173.1:p.Glu1864Asp
LRG_289t1:c.5592G>T
LRG_289:g.103893G>T
LRG_289p1:p.Glu1864Asp
NC_000003.11:g.38592271C>A
NM_198056.2:c.5592G>T

Protein change:

E1810D

Links:

dbSNP: rs794728899

NCBI 1000 Genomes Browser:

rs794728899

Molecular consequence:

NM_000335.5:c.5589G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.5592G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.5538G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.5493G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.5430G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.5535G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.5592G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235538	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Nov 19, 2019)	germline	clinical testing	Citation Link,
SCV000815122	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001472776	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Oct 10, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235538

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Nov 19, 2019)

germline

clinical testing

Citation Link,

SCV000815122

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 4, 2023)

germline

clinical testing

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

SCV001472776

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Uncertain significance
(Oct 10, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
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 GeneDx, SCV000235538.15

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

Description

Has not been previously published in association with SCN5A-related disorders; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 201541; Landrum et al., 2016); No data available from control populations to assess the frequency of this variant; Functional studies do not show that this variant has a significant impact on sodium channel function (Deschenes et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11562792)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000815122.3

#	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 glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1864 of the SCN5A protein (p.Glu1864Asp). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 201541). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is present in population databases (rs794728899, gnomAD 0.01%).

#	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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001472776.2

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

Description

The SCN5A c.5592G>T, p.Glu1864Asp variant (rs794728899), to our knowledge, is not reported in the medical literature but is in ClinVar (Variation ID: 201541). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.615). Due to limited information, the clinical significance of the p.Glu1864Asp variant is uncertain at this time.

#	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: Nov 3, 2024

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