NM_000335.5(SCN5A):c.3214_3215inv (p.Glu1072Ser) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 23, 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:: RCV000598842.15

Allele description [Variation Report for NM_000335.5(SCN5A):c.3214_3215inv (p.Glu1072Ser)]

NM_000335.5(SCN5A):c.3214_3215inv (p.Glu1072Ser)

Genes:

LOC110121269:VISTA enhancer hs2177 [Gene]
SCN5A:sodium voltage-gated channel alpha subunit 5 [Gene - OMIM - HGNC]

Variant type:

Inversion

Cytogenetic location:

3p22.2

Genomic location:

Preferred name:

NM_000335.5(SCN5A):c.3214_3215inv (p.Glu1072Ser)

HGVS:

NC_000003.12:g.38580944_38580945inv
NG_008934.1:g.73728_73729inv
NG_053884.1:g.2683_2684inv
NM_000335.5:c.3214_3215invMANE SELECT
NM_001099404.2:c.3214_3215inv
NM_001099405.2:c.3214_3215inv
NM_001160160.2:c.3214_3215inv
NM_001160161.2:c.3214_3215inv
NM_001354701.2:c.3214_3215inv
NM_198056.3:c.3214_3215inv
NP_000326.2:p.Glu1072Ser
NP_001092874.1:p.Glu1072Ser
NP_001092875.1:p.Glu1072Ser
NP_001153632.1:p.Glu1072Ser
NP_001153633.1:p.Glu1072Ser
NP_001341630.1:p.Glu1072Ser
NP_932173.1:p.Glu1072Ser
NP_932173.1:p.Glu1072Ser
LRG_289t1:c.3214_3215inv
LRG_289:g.73728_73729inv
LRG_289p1:p.Glu1072Ser
NC_000003.11:g.38622435_38622436delinsGA
NC_000003.11:g.38622435_38622436inv
NM_198056.2:c.3214_3215delGAinsTC
NM_198056.2:c.3214_3215delinsTC
NM_198056.2:c.3214_3215inv
NM_198056.3:c.3214_3215delinsTC

Protein change:

E1072S

Links:

Molecular consequence:

NM_000335.5:c.3214_3215inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.3214_3215inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.3214_3215inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.3214_3215inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.3214_3215inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.3214_3215inv - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.3214_3215inv - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000710285	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 17, 2020)	germline	clinical testing	Citation Link,
SCV001401399	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 23, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33221895, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000710285

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jul 17, 2020)

germline

clinical testing

Citation Link,

SCV001401399

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 23, 2024)

germline

clinical testing

PubMed (2)
[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	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

Brugada syndrome genetics is associated with phenotype severity.

Ciconte G, Monasky MM, Santinelli V, Micaglio E, Vicedomini G, Anastasia L, Negro G, Borrelli V, Giannelli L, Santini F, de Innocentiis C, Rondine R, Locati ET, Bernardini A, Mazza BC, Mecarocci V, Ćalović Ž, Ghiroldi A, D'Imperio S, Benedetti S, Di Resta C, Rivolta I, et al.

Eur Heart J. 2021 Mar 14;42(11):1082-1090. doi: 10.1093/eurheartj/ehaa942.

PubMed [citation]

PMID:: 33221895
PMCID:: PMC7955973

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, SCV000710285.3

#	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 as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as variant of uncertain significance but additional evidence is not available (ClinVar Variant ID #503982; Landrum et al., 2016); Deletion of two base pairs and insertion of two different base pairs, which leads to the replacement of a glutamic acid (E) residue with a serine (S) residue at codon position 1072, denoted as E1072S; 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: 33221895)

#	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, SCV001401399.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with serine, which is neutral and polar, at codon 1072 of the SCN5A protein (p.Glu1072Ser). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This missense change has been observed in individual(s) with Brugada syndrome (PMID: 33221895). ClinVar contains an entry for this variant (Variation ID: 503982). 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: May 3, 2025

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