Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Biesecker Lab/Clinical Genomics Section, |
RCV000171698 | SCV000055177 | uncertain significance | Long QT syndrome | 2013-06-24 | criteria provided, single submitter | research | |
| Color Diagnostics, |
RCV001842523 | SCV001340844 | uncertain significance | Cardiac arrhythmia | 2019-09-18 | criteria provided, single submitter | clinical testing | This missense variant replaces valine with phenylalanine at codon 1532 of the SCN5A protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold ≥0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/249164 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Labcorp Genetics |
RCV003657487 | SCV002230323 | uncertain significance | not provided | 2022-07-06 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 191500). This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1532 of the SCN5A protein (p.Val1532Phe). This variant is present in population databases (rs199473618, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. 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 C0"). 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. |
| Victorian Clinical Genetics Services, |
RCV004786488 | SCV005400003 | uncertain significance | Long QT syndrome 3 | 2021-05-06 | 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 and sick sinus syndrome (SSS), whereas gain of function is usually associated with long QT syndrome (LQTS), however some variants simultaneously result in both a loss and gain of function, and have been observed in patients with LQTS, Brugada syndrome, SSS, and patients with a blended phenotype. Additionally, different studies have shown conflicting mechanisms in association with atrial fibrillation (PMID: 29806494, PMID: 19167345, PMID: 26798387). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited, however SSS can be caused by recessive variants (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (74 heterozygotes, 1 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated S1 transmembrane domain in repeat IV (UniProt). (I) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. The p.(Val1532Ile) variant has been reported as likely benign (ClinVar), a VUS (PMID: 28589536), and has been identified in a patient with LQTS (PMID: 19716085). Additionally, the p.(Val1532Ile) and p.(Val1532Ala) variants have also been identified in control individuals in a case/control study (PMID: 25904541). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS (ClinVar) and identified in an individual with coronary artery disease who was specifically selected for not having an arrhythmia, cardiomyopathy, or a family history of sudden death (PMID: 23861362). (I) 0905 - No published segregation evidence has been identified for this variant. (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 |