Submissions for variant NM_000335.5(SCN5A):c.2437-5C>A

gnomAD frequency: 0.00045  dbSNP: rs72549411

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127973	SCV000171561	benign	not specified	2013-12-06	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000127973	SCV000272410	uncertain significance	not specified	2019-01-31	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.2437-5C>A variant in SCN5A has been identified in 1/128 cases of sudden unexplained death (Marcondes 2018). Has also been identified in 0.083% of European chromosomes in gnomAD (dbSNP rs72549411). This variant is also present in ClinVar (ID 039054) with conflicting interpretations (LB/ Uncertain significance). This variant is located in the 3' splice region. Computational tools do not predict a splicing impact, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the c.2437-5C>A variant is uncertain, these data suggest that it is more likely to be benign/its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BP4.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000590814	SCV000291793	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000246661	SCV000319574	likely benign	Cardiovascular phenotype	2018-09-28	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000268911	SCV000444062	uncertain significance	Dilated cardiomyopathy 1E	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000328610	SCV000444063	uncertain significance	Congenital long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000383883	SCV000444064	uncertain significance	Sick sinus syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000294222	SCV000444065	uncertain significance	Progressive familial heart block, type 1A	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000349191	SCV000444066	uncertain significance	Ventricular fibrillation, paroxysmal familial, type 1	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV001094867	SCV000444067	uncertain significance	Brugada syndrome 1	2018-01-12	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000295208	SCV000444068	uncertain significance	Long QT syndrome 3	2018-01-12	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590814	SCV000700025	benign	not provided	2016-01-25	criteria provided, single submitter	clinical testing	Variant summary: This c.2437-5C>A variant affects an intronic non-conserved nucleotide located at a position not widely know to affects splicing. Mutation taster predicts disease causing outcome while 4/5 in silico tools via Alamut predict no effect on normal splicing. It was observed predominantly in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.056% (34/59828 chromosomes) which exceeds the maximal expected allele frequency of a disease causing SCN5A allele (0.01%) indicating the variant to be benign. To our knowledge, the variant has been not reported in affected individuals till date. A clinical diagnostic center classifies variant as Benign via ClinVar (without evidence to independently evaluate), Considering all evidence, the variant was classified as Benign.
Color Diagnostics, LLC DBA Color Health	RCV001842449	SCV000911573	likely benign	Cardiac arrhythmia	2018-06-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590814	SCV001160191	uncertain significance	not provided	2021-04-23	criteria provided, single submitter	clinical testing	The SCN5A c.2437-5C>A variant (rs72549411) is reported in the literature in individuals affected with long QT syndrome (LQTS), hypertrophic cardiomyopathy, or sudden arrhythmic death syndrome (Leong 2017, Lopes 2015, Raju 2019). This variant was found in several affected individuals from a family with LQTS, although it was also found in several family members without symptoms (Leong 2017). The c.2437-5C>A variant is found in the non-Finnish European population with an overall allele frequency of 0.08% (105/125956 alleles) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant does not alter splicing. However, analysis of RNA from an individual carrying this variant suggests it is associated with skipping of SCN5A exon 16 (Leong 2017). Due to limited and conflicting information, the clinical significance of this variant cannot be determined at this time. References: Leong IUS et al. Splice Site Variants in the KCNQ1 and SCN5A Genes: Transcript Analysis as a Tool in Supporting Pathogenicity. J Clin Med Res. 2017 Aug;9(8):709-718. Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. Raju H et al. Next-generation sequencing using microfluidic PCR enrichment for molecular autopsy. BMC Cardiovasc Disord. 2019 Jul 23;19(1):174.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486661	SCV004239660	uncertain significance	Cardiomyopathy	2022-08-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590814	SCV004701347	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	SCN5A: BP4
Roden Lab, Vanderbilt University Medical Center	RCV001094867	SCV005200434	likely benign	Brugada syndrome 1		criteria provided, single submitter	research	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, 3-38586046-G-T was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.000460254 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0.01; 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000295208	SCV005398738	uncertain significance	Long QT syndrome 3	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome 3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are autosomal dominantly inherited; however sick sinus syndrome 1 (MIM#608567) is caused by biallelic variants (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Among individuals with a pathogenic SCN5A variant, approximately 20%-30% have an ECG diagnostic of Brugada syndrome and approximately 80% manifest the characteristic ECG changes when challenged with a sodium channel blocker (PMID: 20301690). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Using non-quantitative method, a study using lymphocyte RNA from heterozygotes showed exon 16 skipping, which is expected to result in an in-frame deletion (PMID: 28725320). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 167 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is expected to affect the annotated ion transport protein domain (DECIPHER). (I) 0704 - Another splice site variant comparable to the one identified in this case has limited previous evidence for pathogenicity. c.2437-2A>C has been reported in an individual clinically suspected for Brugada syndrome. Minigene assay and RT-PCR analysis showed two in-frame deletions in the mutant construct affecting regions within exon 16 (PMID: 34957250). (SP) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported as a VUS, and also likely benign and benign by clinical testing laboratories (ClinVar, VCGS). It has also been reported in individuals with sudden arrhythmic death, unknown cause of death, HCM or Brugada syndrome, but also in unaffected family members (PMIDs: 31337358, 28725320, 25351510, VCGS). (I) 0906 - Segregation evidence for this variant is inconclusive. In one family with a proband who died during sleep, this variant has been reported in her unaffected mother and brother, and two sisters with borderline/distinctly prolonged QTcs (PMID: 28725320). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000590814	SCV001742337	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000127973	SCV001922685	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000590814	SCV001932881	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590814	SCV001954997	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590814	SCV001971014	likely benign	not provided		no assertion criteria provided	clinical testing