Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000766787 | SCV000235590 | uncertain significance | not provided | 2023-03-27 | criteria provided, single submitter | clinical testing | Reported in a proband with sudden death and also identified in this individual's mother; the mother was reported to have QTc prolongation, although no additional details were provided (Blaufox et al., 2012); Reported in an individual with HCM, severe right ventricular hypertrophy, and no noted arrhythmia who was found to harbor several additional cardiogenetic variants in genes associated with her phenotype (Guo et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Functionals studies demonstrated that p.(P627L) expressed in HEK-293 cells resulted in an electrophysiological phenotype similar to the wildtype; nevertheless, it is not clear how well these studies reproduce in vivo conditions (Kapplinger et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27566755, 22360817, 28323875, 25904541) |
| Laboratory for Molecular Medicine, |
RCV000223692 | SCV000540295 | uncertain significance | not specified | 2017-01-31 | criteria provided, single submitter | clinical testing | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper weak segregation data |
| Invitae | RCV000766787 | SCV000637092 | uncertain significance | not provided | 2023-12-10 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 627 of the SCN5A protein (p.Pro627Leu). This variant is present in population databases (rs778522112, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 22360817, 28323875). ClinVar contains an entry for this variant (Variation ID: 201577). 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. Experimental studies have shown that this missense change does not substantially affect SCN5A function (PMID: 25904541). 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. |
| Ambry Genetics | RCV000621604 | SCV000736169 | uncertain significance | Cardiovascular phenotype | 2020-01-22 | criteria provided, single submitter | clinical testing | The p.P627L variant (also known as c.1880C>T), located in coding exon 11 of the SCN5A gene, results from a C to T substitution at nucleotide position 1880. The proline at codon 627 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual with a QTc interval of 427ms and in her mother, who was reported to have a prolonged QTc interval (Blaufox AD et al. Am. J. Cardiol., 2012 May;109:1459-65). In addition, this alteration has been reported in a cohort of long QT syndrome patients (Wilde AA et al. Circulation, 2016 Sep;134:872-82), as well as in an individual with hypertrophic cardiomyopathy who also had variants in other cardiac-related genes (Guo X et al. PLoS ONE, 2017 Mar;12:e0174118). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV001842936 | SCV001359504 | uncertain significance | Cardiac arrhythmia | 2023-03-24 | criteria provided, single submitter | clinical testing | This missense variant replaces proline with leucine at codon 627 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has indicated that this missense does not affect sodium channel function (PMID: 25904541). This variant has been reported in a few individuals affected with long QT syndrome (PMID: 22360817, 27566755), in an individual affected with idiopathic dilated cardiomyopathy (Rodriguez-Garcia et al., 2011), and in two individuals affected with hypertrophic cardiomyopathy who also carried another pathogenic variant in the DSP or MYH7 genes (PMID: 28323875). This variant has been identified in 3/176382 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. |
| Fulgent Genetics, |
RCV002485220 | SCV002781826 | uncertain significance | Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 | 2021-10-12 | criteria provided, single submitter | clinical testing | |
| Stanford Center for Inherited Cardiovascular Disease, |
RCV000223692 | SCV000280464 | uncertain significance | not specified | 2013-06-15 | no assertion criteria provided | clinical testing | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Pro627Leu (P627L; c.1880 C>T) in the SCN5A gene This variant has previously been reported in one unrelated individual with LQTS, with weak segregation data. Blaufox et al. (2012) found Pro627Leu in an LQT3 proband with a prolonged QTc interval. It was also present in the proband’s mother, who likewise had a prolonged QTc interval. Either this proband or the proband’s mother had suffered an aborted sudden cardiac death event (the language in the paper is unclear). Their ancestry is not specified. The study included 81% Caucasian, 11% African-American, and 8% Hispanic families. If the family was Hispanic, there is less ancestry-matched control data available. Variation at several nearby residues has been associated with arrhythmia syndromes, suggesting the functional importance of this protein region: Leu618Phe (LQT3), Leu619Phe (LQT3/Brugada), Arg620Cys (Brugada), Thr632Met (Brugada) (UniProtKB; IRCCS Fondazione Salvatore Maugeri database; testing report referencing HGMD database). This is a conservative amino acid change, resulting in the replacement of a nonpolar, sterically-constrained proline with a nonpolar leucine residue. The proline at this location is highly conserved across mammalian species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. In total the variant has not been seen in >6500 published controls and individuals from publicly available population datasets. This variant is not listed in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. (Our patient’s ancestry is Hispanic.) No variation at this residue is found in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). It is not found in 1000 genomes (http://browser.1000genomes.org/Homo_sapiens/Search/New?db=core) as of December 2, 2012. Blaufox et al. (2012) did not report controls. |