NM_000335.5(SCN5A):c.262A>G (p.Ser88Gly) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 22, 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:: RCV000182922.23

Allele description [Variation Report for NM_000335.5(SCN5A):c.262A>G (p.Ser88Gly)]

NM_000335.5(SCN5A):c.262A>G (p.Ser88Gly)

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.262A>G (p.Ser88Gly)

Other names:

p.S88G:AGC>GGC

HGVS:

NC_000003.12:g.38633046T>C
NG_008934.1:g.21627A>G
NM_000335.5:c.262A>GMANE SELECT
NM_001099404.2:c.262A>G
NM_001099405.2:c.262A>G
NM_001160160.2:c.262A>G
NM_001160161.2:c.262A>G
NM_001354701.2:c.262A>G
NM_198056.3:c.262A>G
NP_000326.2:p.Ser88Gly
NP_001092874.1:p.Ser88Gly
NP_001092875.1:p.Ser88Gly
NP_001153632.1:p.Ser88Gly
NP_001153633.1:p.Ser88Gly
NP_001341630.1:p.Ser88Gly
NP_932173.1:p.Ser88Gly
NP_932173.1:p.Ser88Gly
LRG_289t1:c.262A>G
LRG_289:g.21627A>G
LRG_289p1:p.Ser88Gly
NC_000003.11:g.38674537T>C
NM_001160160.1:c.262A>G
NM_198056.2:c.262A>G

Protein change:

S88G

Links:

dbSNP: rs779961972

NCBI 1000 Genomes Browser:

rs779961972

Molecular consequence:

NM_000335.5:c.262A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.262A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.262A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.262A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.262A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.262A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.262A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000235317	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (May 22, 2017)	germline	clinical testing	Citation Link,
SCV003781747	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32746448, 32880476, 28492532
SCV004154194	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Dec 1, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235317

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(May 22, 2017)

germline

clinical testing

Citation Link,

SCV003781747

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 22, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004154194

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Uncertain significance
(Dec 1, 2022)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic variant burden and adverse outcomes in pediatric cardiomyopathy.

Burstein DS, Gaynor JW, Griffis H, Ritter A, Connor MJO, Rossano JW, Lin KY, Ahrens-Nicklas RC.

Pediatr Res. 2021 May;89(6):1470-1476. doi: 10.1038/s41390-020-1101-5. Epub 2020 Aug 3.

PubMed [citation]

PMID:: 32746448
PMCID:: PMC8256333

Implications of Genetic Testing in Dilated Cardiomyopathy.

Verdonschot JAJ, Hazebroek MR, Krapels IPC, Henkens MTHM, Raafs A, Wang P, Merken JJ, Claes GRF, Vanhoutte EK, van den Wijngaard A, Heymans SRB, Brunner HG.

Circ Genom Precis Med. 2020 Oct;13(5):476-487. doi: 10.1161/CIRCGEN.120.003031. Epub 2020 Sep 3.

PubMed [citation]

PMID:: 32880476

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000235317.11

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

Description

p.Ser88Gly (S88G) AGC>GGC: c.262 A>G in exon 2 of the SCN5A gene (NM_198056.2) The S88G variant in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The S88G variant is a non-conservative amino acid substitution because these residues differ in polarity, charge, size and/or other properties and are more likely to impact secondary structure. Furthermore, the S88G variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations in nearby residues (D84N, Y87C, F93S) have been reported in association with Brugada syndrome, supporting the functional importance of this region of the protein. However, the S88 residue is not conserved across species and in silico analysis predicts S88G is probably benign to the protein structure/function. With the clinical and molecular information available at this time, we cannot definitively determine if S88G is a disease-causing mutation or a rare benign variant. The variant is found in BRUGADA panel(s).

#	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, SCV003781747.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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. 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: 201429). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32746448, 32880476). This variant is present in population databases (rs779961972, gnomAD 0.002%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 88 of the SCN5A protein (p.Ser88Gly).

#	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 CeGaT Center for Human Genetics Tuebingen, SCV004154194.10

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

Description

SCN5A: PM2

#	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		1	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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