Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780740 | SCV000918252 | uncertain significance | not specified | 2018-04-30 | criteria provided, single submitter | clinical testing | Variant summary: SNTA1 c.1425+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. One study (Ueda et al, 2008) reported that SNTA1 connects SCN5A to the nNOSPMCA complex in heart and that a perturbation in SNTA1, stemming from a rare missense mutation (A390V) found in an LQTS patient, selectively disrupted association with PMCA4b, increased SCN5A nitrosylation, and increased late sodium current (INa) in both a noncardiomyocyte heterologous expression system and in native cardiomyocytes. This study supported "gain of function" as the most likely mechanism of action for SNTA1 associated Long QT syndrome (LQT12). Therefore, the effect of the variant of interest, i.e., a splice-site variant on the associated pathophysiology of disease is uncertain. The variant allele was found at a frequency of 2e 05 in 246252 control chromosomes. The observed variant frequency is approximately 2.03 fold of the estimated maximal expected allele frequency for a pathogenic variant in SNTA1 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1425+1G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Ai |
RCV002223937 | SCV002502410 | uncertain significance | not provided | 2021-09-24 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002388407 | SCV002702716 | uncertain significance | Cardiovascular phenotype | 2019-10-24 | criteria provided, single submitter | clinical testing | The c.1425+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the SNTA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, loss of function of SNTA1 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002487609 | SCV002803991 | uncertain significance | Long QT syndrome 12 | 2021-11-24 | criteria provided, single submitter | clinical testing |