ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.2102C>T (p.Pro701Leu) (rs199473147)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171571 SCV000055300 uncertain significance Long QT syndrome 2018-04-05 criteria provided, single submitter research
GeneDx RCV000182996 SCV000235401 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SCN5A gene. The P701L variant has been previously reported in multiple individuals in association with cardiac arrhythmia, including LQTS (Tan et al., 2006; Kapplinger et al., 2009; Zellerhoff et al., 2009; Itoh et al., 2015), Brugada syndrome (Kapplinger et al., 2010), and atrial fibrillation (Maekawa et al., 2005). It has also been observed in one other individual referred cardiomyopathy genetic testing at GeneDx. However, no informative segregation data is available for these published cases or the case observed at GeneDx. Additionally, P701L has been reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing and whose follow-up cardiac evaluation was negative for arrhythmia or cardiomyopathy (Ng et al., 2013). Moreover, patch clamp studies in HEK293 cells showed that P701L, either expressed alone or co-expressed with wild-type SCN5A channels, had no significant impact on sodium currents compared to wild-type SCN5A channels expressed alone (Hoshi et al., 2014). Nevertheless, P701L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and this substitution occurs at a position that is conserved in mammals. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, P701L was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000526384 SCV000637100 uncertain significance Brugada syndrome 2019-06-29 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 701 of the SCN5A protein (p.Pro701Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs199473147, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with long QT syndrome (PMID: 17088455), atrial fibrillation (PMID: 15996170), and was observed in individuals referred for genetic testing for long QT syndrome and Brugada syndrome (PMID: 19716085, 20129283). ClinVar contains an entry for this variant (Variation ID: 67713). This variant has been reported not to substantially affect SCN5A protein function (PMID: 24573164). 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 RCV000619698 SCV000736560 uncertain significance Cardiovascular phenotype 2016-03-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000182996 SCV001153872 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing
Color RCV001179580 SCV001344274 uncertain significance Arrhythmia 2020-01-30 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058480 SCV000090000 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000182996 SCV000924951 uncertain significance not provided 2017-05-18 no assertion criteria provided provider interpretation We have seen this variant in one patient with Brugada type 1 pattern. Testing was performed at Invitae. Given the weak case data, its presence in individuals with diverse phenotypes, weak functional data, and enriched frequency in population databases, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Not including our case, the variant has been seen in at least 2 unrelated cases of LQTS and 1 case of atrial fibrillation. It has also been seen in no more than 3 individuals who have had genetic testing for either LQTS, Brugada or cardiomyopathy. No clinical information available on these individuals. There It has not been reported in any confirmed cases of Brugada syndrome. There is weak case data and no segregation data. Tan et al., 2006 (17088455) identified this variant in a 17yo with long QT syndrome and torsade de pointes recruited from the Netherlands. The variant was reported in 1 individual in the Familion compendium, which includes 2500 patients referred for clinical long QT genetic testing (Kapplinger et al 2009). Of note in considering the cases reported by Kapplinger et al (2009) is the lack of phenotypic data on this cohort, the low yield of 36% (vs. 70% in cohorts with firm diagnoses of long QT), and the lack of clarity regarding which variants were seen with another variant (9% of the cohort had multiple variants). Zellerhoff et al. (2009) reports the variant in a 24yo female who has a QTc of 620ms, history of syncope, and atrial flutter/tachycardia. Itoh et al. (2015) reports one family in which two individuals carry this variant. Subjects were recruited from Europe and Japan on the basis that they had a "known pathogenic variant". The authors do not include clinical data and but do include obligate carriers (who may have been unaffected). Some of the authors overlap with the Tan paper, so the case may be redundant. Kapplinger et al. (2010) identified this variant in one patient referred for Brugada syndrome genetic testing. Similar to the group's 2009 paper, there is lack of clinical data. This case may also overlap with the 2009 paper. Maekawa et al.(2005) identified in this variant in one 60yo Japanese patient with atrial fibrillation. They specifically indicate that patients with LQTS and Brugada syndrome were not included in this study. Functional data suggest that the variant does not have an effect on sodium channel activity (Hoshi et al. 2014). The variant is been seen in 26 of 138,593 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. Specifically the variant has been seen in 12 of 17,209 Latino individuals (MAF = 0.03%), 13 of 63,340 European individuals (MAF = 0.01%), and 1 of 12,017 African individuals (0.004%). The average coverage at that site in gnomAD is 75x. Kapplinger et al (2015) reported this variant in one of their healthy controls.

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