VCV000139061.51 - ClinVar

NM_000335.5(SCN5A):c.3870G>A (p.Leu1290=)

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.

(22)

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(7); Benign(4); Likely benign(6)

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.3870G>A (p.Leu1290=)

Variation ID: 139061 Accession: VCV000139061.51

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38562505 (GRCh38) [ NCBI UCSC ] 3: 38603996 (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	Dec 6, 2016	Oct 20, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.3870G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Leu1290=	synonymous
NM_001099404.2:c.3873G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Leu1291=	synonymous
NM_001099405.2:c.3873G>A	NP_001092875.1:p.Leu1291=	synonymous
NM_001160160.2:c.3870G>A	NP_001153632.1:p.Leu1290=	synonymous
NM_001160161.2:c.3711G>A	NP_001153633.1:p.Leu1237=	synonymous
NM_001354701.2:c.3870G>A	NP_001341630.1:p.Leu1290=	synonymous
NM_198056.3:c.3873G>A	NP_932173.1:p.Leu1291=	synonymous
NC_000003.12:g.38562505C>T
NC_000003.11:g.38603996C>T
NG_008934.1:g.92168G>A
LRG_289:g.92168G>A
LRG_289t1:c.3873G>A	LRG_289p1:p.Leu1291=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:38562504: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.

0.00040 (T)

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

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

Exome Aggregation Consortium (ExAC) 0.00080

The Genome Aggregation Database (gnomAD), exomes 0.00087

Trans-Omics for Precision Medicine (TOPMed) 0.00100

The Genome Aggregation Database (gnomAD) 0.00113

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00152

Links

ClinGen: CA017574 dbSNP: rs41313033 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 specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Jun 24, 2015	RCV000151780.21
Progressive familial heart block, type 1A	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000312012.13
Congenital long QT syndrome	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000370177.13
Long QT syndrome 3	Likely benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000395343.13
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	May 5, 2016	RCV000242801.12
not provided	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Feb 1, 2024	RCV000724707.34
Sick sinus syndrome 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000262735.13
Dilated cardiomyopathy 1E	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000277952.13
Brugada syndrome 1	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 13, 2018	RCV001094936.13
Ventricular fibrillation, paroxysmal familial, type 1	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000369040.13
Cardiac arrhythmia	Benign (2)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV001842454.12
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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 (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Romano-Ward Syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443972.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Benign (May 10, 2012)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000171572.10 First in ClinVar: Jun 23, 2014 Last updated: Dec 06, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Uncertain significance (Apr 09, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000227975.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN5A Number of individuals with the variant: 1 Sex: mixed
Benign (Sep 14, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmia Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000903654.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Jun 24, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000200231.5 First in ClinVar: Jan 30, 2015 Last updated: Dec 15, 2018	Comment: p.Leu1291Leu in Exon 22 of SCN5A: This variant is not expected to have clinical significance because it does not alter an amino acid residue and … (more) p.Leu1291Leu in Exon 22 of SCN5A: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.1% (80/65420) of European chromosomes and 10/15754 South Asian chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs41313033). (less) Number of individuals with the variant: 5
Likely benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Long QT syndrome 3 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443970.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Ventricular fibrillation, paroxysmal familial, type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443975.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Progressive familial heart block, type 1A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443974.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Sick sinus syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443976.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Brugada syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443971.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1E Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000443973.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Likely benign (Feb 28, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001476864.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (1) PubMed: 10508990
Benign (Feb 01, 2024)	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: SCV000262388.9 First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024
Likely benign (May 05, 2016)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318989.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 10508990 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)
Likely benign (-)	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: SCV005200475.1 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, 3-38562505-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.001110512 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0; 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 LB 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, 3-38562505-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.001110512 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0; 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 LB 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
Likely benign (Jun 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004011457.12 First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024	Comment: SCN5A: BP4, BP7 Number of individuals with the variant: 4
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004821008.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 280
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743011.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924740.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927366.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955369.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968563.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

p.Leu1291Leu in Exon 22 of SCN5A: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.1% (80/65420) of European chromosomes and 10/15754 South Asian chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs41313033).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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, 3-38562505-C-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.001110512 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0; 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 LB 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: SCV005200475.1	Publications PubMed (1) Comment: No RNA splicing impact

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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
Sodium channel abnormalities are infrequent in patients with long QT syndrome: identification of two novel SCN5A mutations.	Wattanasirichaigoon D	American journal of medical genetics	1999	PMID: 10508990
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SCN5A	-	-	-	-

Text-mined citations for rs41313033 ...

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.3870G>A (p.Leu1290=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs41313033 ...