NM_000335.5(SCN5A):c.3232T>A (p.Ser1078Thr) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 28, 2024
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:: RCV000183028.12

Allele description [Variation Report for NM_000335.5(SCN5A):c.3232T>A (p.Ser1078Thr)]

NM_000335.5(SCN5A):c.3232T>A (p.Ser1078Thr)

Genes:

LOC110121269:VISTA enhancer hs2177 [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.3232T>A (p.Ser1078Thr)

Other names:

p.S1079T:TCC>ACC

HGVS:

NC_000003.12:g.38579489A>T
NG_008934.1:g.75184T>A
NG_053884.1:g.1228A>T
NM_000335.5:c.3232T>AMANE SELECT
NM_001099404.2:c.3235T>A
NM_001099405.2:c.3235T>A
NM_001160160.2:c.3232T>A
NM_001160161.2:c.3228+1442T>A
NM_001354701.2:c.3232T>A
NM_198056.3:c.3235T>A
NP_000326.2:p.Ser1078Thr
NP_001092874.1:p.Ser1079Thr
NP_001092875.1:p.Ser1079Thr
NP_001153632.1:p.Ser1078Thr
NP_001341630.1:p.Ser1078Thr
NP_932173.1:p.Ser1079Thr
NP_932173.1:p.Ser1079Thr
LRG_289t1:c.3235T>A
LRG_289:g.75184T>A
LRG_289p1:p.Ser1079Thr
NC_000003.11:g.38620980A>T
NM_198056.2:c.3235T>A

Protein change:

S1078T

Links:

dbSNP: rs376183542

NCBI 1000 Genomes Browser:

rs376183542

Molecular consequence:

NM_001160161.2:c.3228+1442T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000335.5:c.3232T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3235T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3235T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3232T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3232T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3235T>A - 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
SCV000235436	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Feb 19, 2018)	germline	clinical testing	Citation Link,
SCV001200425	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 28, 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

SCV000235436

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Feb 19, 2018)

germline

clinical testing

Citation Link,

SCV001200425

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 28, 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	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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000235436.11

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

Description

A variant of uncertain significance has been identified in the SCN5A gene. The S1079T variant has not been previously reported in association with cardiomyopathy or other SCN5A-related disorder, to our knowledge. The S1079T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server; Kapplinger et al., 2015). However, the S1079T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, while missense variants at the same residue (S1079F, S1079Y) have been previously reported in association with SCN5A-related disorders (Itoh et al., 2010; Kapplinger et al., 2010), the clinical significance of these variants also remain to be definitively determined.

#	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 Invitae, SCV001200425.4

#	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 serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1079 of the SCN5A protein (p.Ser1079Thr). This variant is present in population databases (rs376183542, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 201491). 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. 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: Jun 2, 2024

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