VCV000406438.20 - ClinVar

NM_000335.5(SCN5A):c.4068G>A (p.Ala1356=)

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.

(5)

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.

Conflicting classifications of pathogenicity
Uncertain significance(3); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000335.5(SCN5A):c.4068G>A (p.Ala1356=)

Variation ID: 406438 Accession: VCV000406438.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38560321 (GRCh38) [ NCBI UCSC ] 3: 38601812 (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	Apr 17, 2017	Sep 1, 2024	Dec 5, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.4068G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Ala1356=	synonymous
NM_001099404.2:c.4071G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Ala1357=	synonymous
NM_001099405.2:c.4071G>A	NP_001092875.1:p.Ala1357=	synonymous
NM_001160160.2:c.4068G>A	NP_001153632.1:p.Ala1356=	synonymous
NM_001160161.2:c.3909G>A	NP_001153633.1:p.Ala1303=	synonymous
NM_001354701.2:c.4068G>A	NP_001341630.1:p.Ala1356=	synonymous
NM_198056.3:c.4071G>A	NP_932173.1:p.Ala1357=	synonymous
NC_000003.12:g.38560321C>T
NC_000003.11:g.38601812C>T
NG_008934.1:g.94352G>A
LRG_289:g.94352G>A
LRG_289t1:c.4071G>A	LRG_289p1:p.Ala1357=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:38560320:C:T

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

functionally_normal; Sequence Ontology [ SO:0002219]

No RNA splicing impact [submitted by Roden Lab, Vanderbilt University Medical Center]

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.

0.00020 (T)

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

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA062789 dbSNP: rs187370816 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.
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Aug 10, 2016	RCV000621220.11
Cardiac arrhythmia	Likely benign (1)	criteria provided, single submitter	Dec 5, 2023	RCV001841358.11
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 3, 2023	RCV002269271.11
Brugada syndrome 1	Uncertain significance (1)	criteria provided, single submitter	-	RCV004698496.1

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.
Uncertain significance (Jan 20, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002552918.2 First in ClinVar: Jul 30, 2022 Last updated: Mar 04, 2023	Comment: Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant … (more) Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar (ClinVar Variant ID# 406438) (less)
Likely benign (Dec 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001343721.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024
Uncertain significance (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: SCV000545072.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024	Comment: This variant is present in population databases (rs187370816, gnomAD 0.01%). This sequence change affects codon 1357 of the SCN5A mRNA. It is a 'silent' change, … (more) This variant is present in population databases (rs187370816, gnomAD 0.01%). This sequence change affects codon 1357 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 406438). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. (less)
Likely benign (Aug 10, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000737142.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research, in vitro	Brugada syndrome 1 Affected status: unknown, not applicable Allele origin: germline, not applicable	Roden Lab, Vanderbilt University Medical Center Accession: SCV005200427.1 First in ClinVar: Sep 01, 2024 Last updated: Sep 01, 2024 Comment: We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework … (more) We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38560321-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.0000197 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.688; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have no impact on splicing (BS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). We do not apply benign splicing functional data to missense variants. In aggregate, we therefore classify this variant as VUS using these collective data. (less)	Publications: PubMed (1) PubMed: 37732247 Comment: We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework … (more) We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38560321-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.0000197 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.688; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have no impact on splicing (BS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). We do not apply benign splicing functional data to missense variants. In aggregate, we therefore classify this variant as VUS using these collective data. (less) Observation 1: Observation 2: Comment on evidence: Functional evidence assertions with RNA-splicing scores. Benign RNA-splicing scores were not applied to missense variants. Method: Calibrated RNA splicing assay, ParSE-seq. Outcomes derived from OddsPath quantification on control variants. Result: No RNA splicing impact

Comment:

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported in ClinVar (ClinVar Variant ID# 406438)

Comment:

This variant is present in population databases (rs187370816, gnomAD 0.01%). This sequence change affects codon 1357 of the SCN5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SCN5A protein. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 406438). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38560321-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.0000197 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.688; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have no impact on splicing (BS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). We do not apply benign splicing functional data to missense variants. In aggregate, we therefore classify this variant as VUS using these collective data.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
functionally_normal (SO:0002219)	Method not provided Calibrated RNA splicing assay, ParSE-seq. Outcomes derived from OddsPath quantification on control variants. Method citation(s): PubMed(1)	Result not provided No RNA splicing impact	Roden Lab, Vanderbilt University Medical Center Accession: SCV005200427.1	Publications PubMed (1) Comment: No RNA splicing impact

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
ParSE-seq: A Calibrated Multiplexed Assay to Facilitate the Clinical Classification of Putative Splice-altering Variants.	O'Neill MJ	medRxiv : the preprint server for health sciences	2023	PMID: 37732247

Text-mined citations for rs187370816 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000335.5(SCN5A):c.4068G>A (p.Ala1356=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs187370816 ...