ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.4057G>A (p.Val1353Met) (rs199473233)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183060 SCV000235469 uncertain significance not provided 2017-08-18 criteria provided, single submitter clinical testing The V1353M variant has been reported in two individuals referred for Brugada syndrome genetic testing, and a sudden infant death case, though this infant was categorized into a sub-cohort which included infants with slight infections before death, preterm birth or other deviations from a normal personal and family history (Kapplinger et al., 2010; Walsh et al., 2014; Neubauer et al., 2017). It has also been reported in one individual from a cohort recruited for non-antiarrhythmic drug exposure phenotypes (Van Driest et al., 2016). Additionally, it has been identified independently and/or in conjunction with additional cardiogenetic variants in individuals referred for Brugada syndrome genetic testing at GeneDx. Of note, molecular evaluation of one family suggested lack of segregation with a reported diagnosis of Brugada syndrome in one first-degree relative of the proband. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the V1353M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. The Exome Aggregation Consortium reports V1353M was observed in 1/8654 (0.01%) alleles from individuals of East Asian background (Lek et al., 2016).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000183060 SCV001153862 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
Invitae RCV000058636 SCV001211979 uncertain significance Brugada syndrome 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 1353 of the SCN5A protein (p.Val1353Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs199473233, ExAC 0.01%). This variant has been observed in several individuals affected with clinical features of SCN5A-related disease (PMID: 20129283, 30086531, 29540472, 28074886). ClinVar contains an entry for this variant (Variation ID: 67857). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV001144668 SCV001305281 uncertain significance Brugada syndrome 1 2017-04-28 criteria provided, single submitter clinical testing 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001144669 SCV001305282 uncertain significance Dilated cardiomyopathy 1E 2017-04-28 criteria provided, single submitter clinical testing 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001144670 SCV001305283 uncertain significance Long QT syndrome 3 2017-04-28 criteria provided, single submitter clinical testing 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001144671 SCV001305284 uncertain significance Paroxysmal familial ventricular fibrillation 1 2017-04-28 criteria provided, single submitter clinical testing 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001146613 SCV001307364 uncertain significance Progressive familial heart block, type 1A 2017-04-28 criteria provided, single submitter clinical testing 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001146614 SCV001307365 benign Sick sinus syndrome 1, autosomal recessive 2017-04-28 criteria provided, single submitter clinical testing 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Color RCV001190158 SCV001357584 uncertain significance Arrhythmia 2018-12-11 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058636 SCV000090156 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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