Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003764737 | SCV002305110 | uncertain significance | not provided | 2024-02-26 | criteria provided, single submitter | clinical testing | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 138 of the SCN5A protein (p.Met138Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy and atrial fibrillation (PMID: 18378609). ClinVar contains an entry for this variant (Variation ID: 67865). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. |
| All of Us Research Program, |
RCV003996540 | SCV004841065 | uncertain significance | Cardiac arrhythmia | 2023-10-02 | criteria provided, single submitter | clinical testing | This variant replaces methionine with isoleucine at codon 138 in the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant found in a highly conserved transmembrane domain region (a.a. 131-161). Rare non-truncating variants in this region have been shown to be significantly overrepresented in SCN5A-associated disorders (PMID: 32893267). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with atrial fibrillation and dilated cardiomyopathy (PMID: 18378609) and another individual suspected of epilepsy (PMID: 31696929). This variant has been identified in 1/243916 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. |
| Ambry Genetics | RCV004017379 | SCV004849280 | uncertain significance | Cardiovascular phenotype | 2019-06-05 | criteria provided, single submitter | clinical testing | The c.414G>A (p.M138I) alteration is located in exon 4 (coding exon 3) of the SCN5A gene. This alteration results from a G to A substitution at nucleotide position 414, causing the methionine (M) at amino acid position 138 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Cardiovascular Biomedical Research Unit, |
RCV000148866 | SCV000090164 | not provided | Atrial fibrillation | no assertion provided | literature only | This variant has been reported as associated with Atrial fibrillation in the following publications (PMID:18378609). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. | |
| CSER _CC_NCGL, |
RCV000148866 | SCV000190610 | uncertain significance | Atrial fibrillation | 2014-06-01 | no assertion criteria provided | research |