ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1880C>T (p.Pro627Leu) (rs778522112)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621604 SCV000736169 uncertain significance Cardiovascular phenotype 2017-12-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000766787 SCV000235590 uncertain significance not provided 2017-07-24 criteria provided, single submitter clinical testing The P627L variant of uncertain significance in the SCN5A gene has been previously described in a proband with sudden death and this individual’s mother, who was reported to have QTc prolongation, although no additional details were provided (Blaufox et al., 2012). The P627L variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition, P627L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution also occurs at a position that is conserved across species. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, Kapplinger et al. (2015) demonstrated that P627L expressed in HEK-293 cells resulted in an electrophysiological phenotype similar to the wildtype. Moreover, P627L has also been 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). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000534878 SCV000637092 uncertain significance Brugada syndrome 2018-01-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 627 of the SCN5A protein (p.Pro627Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs778522112, ExAC 0.002%). This variant has been reported in the literature in two individuals from a family with prolonged QTc interval (PMID: 22360817) and in combination with variants in other cardiovascular-related genes in an individual with hypertrophic cardiomyopathy and severe right ventricular hypertrophy (PMID: 28323875). ClinVar contains an entry for this variant (Variation ID: 201577). A study combining electrophysiology and in silico data suggested that this missense change does not affect protein 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized 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
Stanford Center for Inherited Cardiovascular Disease,Stanford University 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.

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