ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.2437-5C>A (rs72549411)

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Total submissions: 14
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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,Partners HealthCare 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.
Invitae RCV000226685 SCV000291793 likely benign Brugada syndrome 2020-11-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000246661 SCV000319574 likely benign Cardiovascular phenotype 2018-09-28 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign)
Illumina Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000328610 SCV000444063 uncertain significance Romano-Ward syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000383883 SCV000444064 uncertain significance Sick sinus syndrome 1, autosomal recessive 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 Clinical Services Laboratory,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 Clinical Services Laboratory,Illumina RCV000349191 SCV000444066 uncertain significance Paroxysmal familial ventricular fibrillation 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 Clinical Services Laboratory,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 Clinical Services Laboratory,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 Health, Inc RCV000776286 SCV000911573 likely benign Arrhythmia 2018-06-18 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282785 SCV001160191 uncertain significance none provided 2019-11-11 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 causes skipping of SCN5A exon 16 (Leong 2017). However, due to 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.

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