VCV002749678.2 - ClinVar

NM_000335.5(SCN5A):c.3493del (p.Asp1165fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000335.5(SCN5A):c.3493del (p.Asp1165fs)

Variation ID: 2749678 Accession: VCV002749678.2

Type and length

Deletion, 1 bp

Location

Cytogenetic: 3p22.2 3: 38576676 (GRCh38) [ NCBI UCSC ] 3: 38618167 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 14, 2024	May 1, 2024	Dec 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.3493del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Asp1165fs	frameshift
NM_001099404.2:c.3496del MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Asp1166fs	frameshift
NM_001099405.2:c.3496del	NP_001092875.1:p.Asp1166fs	frameshift
NM_001160160.2:c.3493del	NP_001153632.1:p.Asp1165fs	frameshift
NM_001160161.2:c.3334del	NP_001153633.1:p.Asp1112fs	frameshift
NM_001354701.2:c.3493del	NP_001341630.1:p.Asp1165fs	frameshift
NM_198056.2:c.3496delG
NM_198056.3:c.3496del	NP_932173.1:p.Asp1166fs	frameshift
NR_176299.1:n.4242del		non-coding transcript variant
NC_000003.12:g.38576677del
NC_000003.11:g.38618168del
NG_008934.1:g.77997del
LRG_289:g.77997del
LRG_289t1:c.3495del	LRG_289p1:p.Asp1166Thrfs
LRG_289t2:c.3492del	LRG_289p2:p.Asp1165Thrfs
LRG_289t3:c.3495del	LRG_289p3:p.Asp1166Thrfs

... more HGVS ... less HGVS

Protein change

D1165fs, D1112fs, D1166fs

Other names

Canonical SPDI

NC_000003.12:38576675:CC:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SCN5A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3783	4225

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Aug 3, 2023	RCV003568552.2
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2023	RCV004369380.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Aug 03, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004312337.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 20129283‚ 22789973 Comment: For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. … (more) For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp1166Thrfs*49) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973). (less)
Pathogenic (Dec 13, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV005031310.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: The c.3496delG pathogenic mutation, located in coding exon 18 of the SCN5A gene, results from a deletion of one nucleotide at nucleotide position 3496, causing … (more) The c.3496delG pathogenic mutation, located in coding exon 18 of the SCN5A gene, results from a deletion of one nucleotide at nucleotide position 3496, causing a translational frameshift with a predicted alternate stop codon (p.D1166Tfs*49). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)

Comment:

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp1166Thrfs*49) in the SCN5A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCN5A are known to be pathogenic (PMID: 20129283, 22789973).

Comment:

The c.3496delG pathogenic mutation, located in coding exon 18 of the SCN5A gene, results from a deletion of one nucleotide at nucleotide position 3496, causing a translational frameshift with a predicted alternate stop codon (p.D1166Tfs*49). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Brugada syndrome 2012.	Berne P	Circulation journal : official journal of the Japanese Circulation Society	2012	PMID: 22789973
An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.	Kapplinger JD	Heart rhythm	2010	PMID: 20129283

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_000335.5(SCN5A):c.3493del (p.Asp1165fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...