VCV000067683.52 - ClinVar

NM_000335.5(SCN5A):c.1715C>A (p.Ala572Asp)

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.

(26)

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.

Benign/Likely benign

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.1715C>A (p.Ala572Asp)

Variation ID: 67683 Accession: VCV000067683.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p22.2 3: 38603887 (GRCh38) [ NCBI UCSC ] 3: 38645378 (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 6, 2015	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000335.5:c.1715C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000326.2:p.Ala572Asp	missense
NM_001099404.2:c.1715C>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001092874.1:p.Ala572Asp	missense
NM_001099405.2:c.1715C>A	NP_001092875.1:p.Ala572Asp	missense
NM_001160160.2:c.1715C>A	NP_001153632.1:p.Ala572Asp	missense
NM_001160161.2:c.1715C>A	NP_001153633.1:p.Ala572Asp	missense
NM_001354701.2:c.1715C>A	NP_001341630.1:p.Ala572Asp	missense
NM_198056.3:c.1715C>A	NP_932173.1:p.Ala572Asp	missense
NC_000003.12:g.38603887G>T
NC_000003.11:g.38645378G>T
NG_008934.1:g.50786C>A
LRG_289:g.50786C>A
LRG_289t1:c.1715C>A	LRG_289p1:p.Ala572Asp
LRG_289t2:c.1715C>A
	Q14524:p.Ala572Asp

... more HGVS ... less HGVS

Protein change

A572D

Other names

p.A572D:GCC>GAC

Canonical SPDI

NC_000003.12:38603886:G:T

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.

0.00180 (T)

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

1000 Genomes Project 30x 0.00125

Trans-Omics for Precision Medicine (TOPMed) 0.00126

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00168

1000 Genomes Project 0.00180

Links

dbSNP: rs36210423 ClinGen: CA015266 UniProtKB: Q14524#VAR_055178 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.
Congenital long QT syndrome	not provided (1)	no classification provided	-	RCV000058447.11
not specified	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	Dec 11, 2017	RCV000151795.19
Left ventricular noncompaction cardiomyopathy	Likely benign (1)	no assertion criteria provided	Aug 29, 2014	RCV000157480.9
Ventricular fibrillation, paroxysmal familial, type 1	Likely benign (2)	criteria provided, single submitter	Apr 27, 2017	RCV000143951.14
Cardiac arrest	Likely benign (1)	no assertion criteria provided	Aug 29, 2014	RCV000157481.9
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Oct 1, 2015	RCV000244195.11
Dilated cardiomyopathy 1E	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000360867.13
Sick sinus syndrome 1	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000264595.13
Long QT syndrome 3	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000268589.13
not provided	Benign/Likely benign (7)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000438831.36
Progressive familial heart block, type 1A	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV000326049.13
Arrhythmogenic right ventricular cardiomyopathy	Likely benign (1)	criteria provided, single submitter	Aug 16, 2017	RCV000852965.9
Brugada syndrome 1	Likely benign (1)	criteria provided, single submitter	Apr 27, 2017	RCV001094811.12
Cardiac arrhythmia	Benign (1)	criteria provided, single submitter	Mar 19, 2018	RCV001842295.10
Atrial fibrillation, familial, 10 Brugada syndrome 1 Dilated cardiomyopathy 1E Long QT syndrome 3 Progressive familial heart block, type 1A SUDDEN INFANT DEATH SYNDROME Sick sinus syndrome 1 Ventricular fibrillation, paroxysmal familial, type 1	Benign (1)	criteria provided, single submitter	Sep 6, 2021	RCV002504971.8
Cardiomyopathy	Benign (1)	criteria provided, single submitter	Mar 3, 2023	RCV003486630.1
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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.
Likely Benign (Jan 03, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000510889.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Converted during submission to Likely benign.
Likely benign (Apr 18, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000843709.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (16) PubMed: 20403459‚ 20875080‚ 12820704‚ 27287068‚ 19412328‚ 28781330‚ 26749013‚ 16540748‚ 18452873‚ 29032884‚ 23008441‚ 23098067‚ 22378279‚ 24653702‚ 26209461‚ 28265756
Benign (Mar 19, 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: SCV000911065.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (Aug 12, 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: SCV000200252.5 First in ClinVar: Jan 30, 2015 Last updated: Jun 03, 2019	Publications: PubMed (7) PubMed: 23008441‚ 20403459‚ 17161064‚ 23098067‚ 12820704‚ 18071069‚ 17210839 Comment: p.Ala572Asp in exon 12 of SCN5A: This variant was identified in 3.9% (257/6618) Finnish chromosomes including 5 homozygous individuals by the Exome Aggregation Consortium (ExAC, … (more) p.Ala572Asp in exon 12 of SCN5A: This variant was identified in 3.9% (257/6618) Finnish chromosomes including 5 homozygous individuals by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs36210423) and was re ported at slightly lower frequencies in control cohorts across multiple studies investigating the genetic cause of LQTS and related clinical entities (Mank-Seym our 2006, Arnestad 2007, Albert 2008, Tester 2010). There is a possibility that the p.Ala572Asp variant may have a minor impact on protein function (Albert 2008 , Tester 2010, Koval 2012); however, these in vitro assays may not accurately re present biological function. Although a modifying role in disease cannot be full y excluded, this variant is likely benign. (less) Number of individuals with the variant: 3
Benign (Mar 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004239655.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Benign (Jan 31, 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: SCV000291783.9 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Benign (Dec 11, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000920198.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (4) PubMed: 20403459‚ 27287068‚ 18071069‚ 12820704 Comment: Variant summary: The SCN5A c.1715C>A (p.Ala572Asp) variant located in the cytoplasmic region between domains I and II of Nav1.5 (Ortiz-Bonnin_2016) involves the alteration of a … (more) Variant summary: The SCN5A c.1715C>A (p.Ala572Asp) variant located in the cytoplasmic region between domains I and II of Nav1.5 (Ortiz-Bonnin_2016) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies show the variant could have a gain-of-function implication (Ortiz-Bonin_2016), an affect on recovery time (Albert_2008), or acts like wild type SCN5A, although in the context of a certain genotype such as the SCN5A polymorphism H588R moderate dysfunction was observed (Tester_2010). Overall, the authors indicate that the variant is not associated with the LQTS phenotype. This variant was found in 1486/279922 control chromosomes (23 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.038676 (997/25778). This frequency is about 387 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. Multiple publications have cited the variant of interest in affected individuals. One family reported by Paulussen_2003 found the variant to be in two unaffected family members, with the proband carrying the variant and another pathogenic KCNQ1 variant, V254M, while Ortiz-Bonnin_2016 reported an affected family member that did not carry the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, based on reports of co-occurrence with a pathogenic variant in another gene, lack of co-segregation with disease phenotype, and an unexpectedly high frequency in controls, this variant is classified as benign, although the possibility of a modifier effect in certain genetic backgrounds cannot be ruled out. (less)
Likely benign (Aug 16, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995714.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
Likely benign (Apr 27, 2017)	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: SCV000444119.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	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: SCV000444120.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	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: SCV000444124.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	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: SCV000444122.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	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: SCV000444123.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Apr 27, 2017)	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: SCV000444121.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Sep 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Progressive familial heart block, type 1A SUDDEN INFANT DEATH SYNDROME Brugada syndrome 1 Dilated cardiomyopathy 1E Ventricular fibrillation, paroxysmal familial, type 1 Long QT syndrome 3 Sick sinus syndrome 1 Atrial fibrillation, familial, 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002808373.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Apr 22, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000235296.6 First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 23008441, 22378279, 20403459, 12820704, 27243970, 27153395, 27287068, 27930701, 18452873, 28781330, 29672598, 29214556, 28988457, 29032884, 32880476)
Benign (Oct 01, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000317847.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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)
Benign (Jul 01, 2024)	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: SCV002496801.18 First in ClinVar: Apr 11, 2022 Last updated: Oct 20, 2024	Comment: SCN5A: BS1, BS2 Number of individuals with the variant: 9
Likely benign (Aug 29, 2014)	no assertion criteria provided Method: clinical testing	Paroxysmal familial ventricular fibrillation Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000188831.2 First in ClinVar: Sep 07, 2014 Last updated: Feb 06, 2015	Publications: PubMed (1) PubMed: 20403459 Number of individuals with the variant: 1
Likely benign (Aug 29, 2014)	no assertion criteria provided Method: clinical testing	Left ventricular noncompaction cardiomyopathy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207225.1 First in ClinVar: Feb 06, 2015 Last updated: Feb 06, 2015	Publications: PubMed (1) PubMed: 20403459 Number of individuals with the variant: 1
Likely benign (Aug 29, 2014)	no assertion criteria provided Method: clinical testing	Cardiac Arrest Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207226.1 First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015	Publications: PubMed (1) PubMed: 20403459 Number of individuals with the variant: 1
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: SCV001743547.3 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: SCV001925392.1 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	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001932901.1 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	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: SCV001955001.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: literature only	Congenital long QT syndrome Affected status: unknown Allele origin: germline	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust Accession: SCV000089967.3 First in ClinVar: Oct 22, 2013 Last updated: Oct 09, 2016	Publications: PubMed (9) PubMed: 22581653‚ 12354768‚ 12820704‚ 15466642‚ 15840476‚ 17161064‚ 17210839‚ 18071069‚ 20403459 Comment: This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12354768;PMID:12820704;PMID:15466642;PMID:15840476;PMID:17161064;PMID:17210839;PMID:18071069;PMID:20403459). This is a literature report, and does not necessarily … (more) This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12354768;PMID:12820704;PMID:15466642;PMID:15840476;PMID:17161064;PMID:17210839;PMID:18071069;PMID:20403459). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. (less)
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Comment:

p.Ala572Asp in exon 12 of SCN5A: This variant was identified in 3.9% (257/6618) Finnish chromosomes including 5 homozygous individuals by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs36210423) and was re ported at slightly lower frequencies in control cohorts across multiple studies investigating the genetic cause of LQTS and related clinical entities (Mank-Seym our 2006, Arnestad 2007, Albert 2008, Tester 2010). There is a possibility that the p.Ala572Asp variant may have a minor impact on protein function (Albert 2008 , Tester 2010, Koval 2012); however, these in vitro assays may not accurately re present biological function. Although a modifying role in disease cannot be full y excluded, this variant is likely benign.

Comment:

Variant summary: The SCN5A c.1715C>A (p.Ala572Asp) variant located in the cytoplasmic region between domains I and II of Nav1.5 (Ortiz-Bonnin_2016) involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies show the variant could have a gain-of-function implication (Ortiz-Bonin_2016), an affect on recovery time (Albert_2008), or acts like wild type SCN5A, although in the context of a certain genotype such as the SCN5A polymorphism H588R moderate dysfunction was observed (Tester_2010). Overall, the authors indicate that the variant is not associated with the LQTS phenotype. This variant was found in 1486/279922 control chromosomes (23 homozygotes), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.038676 (997/25778). This frequency is about 387 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. Multiple publications have cited the variant of interest in affected individuals. One family reported by Paulussen_2003 found the variant to be in two unaffected family members, with the proband carrying the variant and another pathogenic KCNQ1 variant, V254M, while Ortiz-Bonnin_2016 reported an affected family member that did not carry the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, based on reports of co-occurrence with a pathogenic variant in another gene, lack of co-segregation with disease phenotype, and an unexpectedly high frequency in controls, this variant is classified as benign, although the possibility of a modifier effect in certain genetic backgrounds cannot be ruled out.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This alteration is classified as 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:

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12354768;PMID:12820704;PMID:15466642;PMID:15840476;PMID:17161064;PMID:17210839;PMID:18071069;PMID:20403459). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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
The genetics underlying idiopathic ventricular fibrillation: A special role for catecholaminergic polymorphic ventricular tachycardia?	Leinonen JT	International journal of cardiology	2018	PMID: 29032884
Prolonged Right Ventricular Ejection Delay in Brugada Syndrome Depends on the Type of SCN5A Variant　- Electromechanical Coupling Through Tissue Velocity Imaging as a Bridge Between Genotyping and Phenotyping.	Van Malderen SCH	Circulation journal : official journal of the Japanese Circulation Society	2017	PMID: 28781330
Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes.	Chadda KR	Pflugers Archiv : European journal of physiology	2017	PMID: 28265756
Electrophysiological characterization of a large set of novel variants in the SCN5A-gene: identification of novel LQTS3 and BrS mutations.	Ortiz-Bonnin B	Pflugers Archiv : European journal of physiology	2016	PMID: 27287068
Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention.	Goldman AM	Epilepsia	2016	PMID: 26749013
The multi-faceted aspects of the complex cardiac Nav1.5 protein in membrane function and pathophysiology.	Detta N	Biochimica et biophysica acta	2015	PMID: 26209461
CaMKII-dependent regulation of cardiac Na(+) homeostasis.	Grandi E	Frontiers in pharmacology	2014	PMID: 24653702
Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing.	Stattin EL	BMC cardiovascular disorders	2012	PMID: 23098067
Ca2+/calmodulin-dependent protein kinase II-based regulation of voltage-gated Na+ channel in cardiac disease.	Koval OM	Circulation	2012	PMID: 23008441
High prevalence of genetic variants previously associated with LQT syndrome in new exome data.	Refsgaard L	European journal of human genetics : EJHG	2012	PMID: 22378279
Post-mortem review and genetic analysis of sudden unexpected death in epilepsy (SUDEP) cases.	Tu E	Brain pathology (Zurich, Switzerland)	2011	PMID: 20875080
Epidemiologic, molecular, and functional evidence suggest A572D-SCN5A should not be considered an independent LQT3-susceptibility mutation.	Tester DJ	Heart rhythm	2010	PMID: 20403459
Coding sequence mutations identified in MYH7, TNNT2, SCN5A, CSRP3, LBD3, and TCAP from 313 patients with familial or idiopathic dilated cardiomyopathy.	Hershberger RE	Clinical and translational science	2008	PMID: 19412328
Prevalence of early-onset atrial fibrillation in congenital long QT syndrome.	Johnson JN	Heart rhythm	2008	PMID: 18452873
Cardiac sodium channel gene variants and sudden cardiac death in women.	Albert CM	Circulation	2008	PMID: 18071069
Prevalence of long-QT syndrome gene variants in sudden infant death syndrome.	Arnestad M	Circulation	2007	PMID: 17210839
Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes.	Mank-Seymour AR	American heart journal	2006	PMID: 17161064
The long QT syndrome family of cardiac ion channelopathies: a HuGE review.	Modell SM	Genetics in medicine : official journal of the American College of Medical Genetics	2006	PMID: 16540748
Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.	Tester DJ	Heart rhythm	2005	PMID: 15840476
Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes.	Choi G	Circulation	2004	PMID: 15466642
Mutation analysis in congenital Long QT Syndrome--a case with missense mutations in KCNQ1 and SCN5A.	Paulussen A	Genetic testing	2003	PMID: 12820704
A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency.	Paulussen A	The Journal of biological chemistry	2002	PMID: 12354768
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Text-mined citations for rs36210423 ...

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.1715C>A (p.Ala572Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs36210423 ...