NM_000335.5(SCN5A):c.2859C>G (p.Asp953Glu) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Aug 28, 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:: RCV000183014.3

Allele description [Variation Report for NM_000335.5(SCN5A):c.2859C>G (p.Asp953Glu)]

NM_000335.5(SCN5A):c.2859C>G (p.Asp953Glu)

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.2859C>G (p.Asp953Glu)

Other names:

p.D953E:GAC>GAG

HGVS:

NC_000003.12:g.38581300G>C
NG_008934.1:g.73373C>G
NG_053884.1:g.3039G>C
NM_000335.5:c.2859C>GMANE SELECT
NM_001099404.2:c.2859C>G
NM_001099405.2:c.2859C>G
NM_001160160.2:c.2859C>G
NM_001160161.2:c.2859C>G
NM_001354701.2:c.2859C>G
NM_198056.3:c.2859C>G
NP_000326.2:p.Asp953Glu
NP_001092874.1:p.Asp953Glu
NP_001092875.1:p.Asp953Glu
NP_001153632.1:p.Asp953Glu
NP_001153633.1:p.Asp953Glu
NP_001341630.1:p.Asp953Glu
NP_932173.1:p.Asp953Glu
NP_932173.1:p.Asp953Glu
LRG_289t1:c.2859C>G
LRG_289:g.73373C>G
LRG_289p1:p.Asp953Glu
NC_000003.11:g.38622791G>C
NM_198056.2:c.2859C>G

Protein change:

D953E

Links:

dbSNP: rs762818132

NCBI 1000 Genomes Browser:

rs762818132

Molecular consequence:

NM_000335.5:c.2859C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099404.2:c.2859C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001099405.2:c.2859C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160160.2:c.2859C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001160161.2:c.2859C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354701.2:c.2859C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198056.3:c.2859C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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dynamin-1-like protein isoform q [Mus musculus]
dynamin-1-like protein isoform q [Mus musculus]
gi|2228568472|ref|NP_001392190.1|

Protein
Edmundoa perplexa NADH dehydrogenase subunit F (ndhF) gene, partial cds; chlorop...
Edmundoa perplexa NADH dehydrogenase subunit F (ndhF) gene, partial cds; chloroplast
gi|341942339|gb|HQ895746.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235421	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Apr 8, 2014)	germline	clinical testing	Citation Link,
SCV000760265	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 28, 2023)	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

SCV000235421

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Apr 8, 2014)

germline

clinical testing

Citation Link,

SCV000760265

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 28, 2023)

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV000235421.10

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

Description

p.Asp953Glu (GAC>GAG): c.2859 C>G in exon 17 of the SCN5A gene (NM_198056.2) The D953E variant has not been published as a mutation or as a benign polymorphism to our knowledge. The D953E variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is highly conserved across species. In silico analysis predicts this variant is possibly damaging to the protein structure/function. A missense mutation in nearby residues (Q960K) has been reported in association with LQTS, supporting the functional importance of this region of the protein. However, the D953E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY 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, SCV000760265.5

#	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 aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 953 of the SCN5A protein (p.Asp953Glu). This variant is present in population databases (rs762818132, gnomAD 0.002%). 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: 201482). 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 disruptive. 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: Oct 26, 2024

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