ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.680T>C (p.Leu227Pro) (rs760011764)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182943 SCV000235339 likely pathogenic not provided 2012-12-20 criteria provided, single submitter clinical testing p.Leu227Pro (CTG>CCG): c.680 T>C in exon 6 of the SCN5A gene (NM_198056.2 )The Leu227Pro variant in the SCN5A gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Leu227Pro results in a semi-conservative amino acid substitution of a nonpolar Leucine with a nonpolar but sterically-constrained Proline at a position that is conserved across species. In silico analysis predicts Leu227Pro is damaging to the protein structure/function. Mutations in nearby residues (Arg225Gln, Arg225Trp, Ala226Asp, Ala226Val, Ile230Thr, Ile230Val) have been reported in association with arrhythmia, further supporting the functional importance of this region of the protein. Leu227Pro was absent from the 1000 Genomes database, and the NHLBI ESP Exome Variant Server reports Leu227Pro was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. However, data from ethnically-matched control individuals were not available to assess for a population-specific benign variant.In summary, Leu227Pro is a good candidate for a disease-causing mutation. The variant is found in DCM,ARRHYTHMIA panel(s).
Invitae RCV000229800 SCV000291831 uncertain significance Brugada syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 227 of the SCN5A protein (p.Leu227Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs760011764, ExAC 0.02%). This variant has been observed in an individual affected with Brugada syndrome (PMID: 28127136). ClinVar contains an entry for this variant (Variation ID: 201441). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223856 SCV000280483 uncertain significance not specified 2012-12-02 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. GENETIC TESTING: p.Leu227Pro (L227P; c.680 T>C) in the SCN5A gene We have seen this variant in a patient with severe sinus node dysfunction of unclear etiology, with additional conduction system disease. The patient carried other rare variants. This variant is completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism. Nearby variants (within 10 amino acids) have been associated with disease: T220I with sick sinus syndrome (IRCCS Fondazione Salvatore Maugeri database, citing Benson et al. 2003) and DCM (IRCCS Fondazione Salvatore Maugeri database, citing Olson et al. 2005), R225W with cardiac conduction disease (IRCCS Fondazione Salvatore Maugeri database, citing Bezzina et al. 2003; HGMD via GeneDx), R225Q with LQT3 (IRCCS Fondazione Salvatore Maugeri database, citing Millat et al. 2006; HGMD via GeneDx), A226V in Brugada (UniProtKB, HGMD via GeneDx), A226D (HGMD via GeneDx), I230V in Brugada (UniProtKB, HGMD via GeneDx), I230T (HGMD via GeneDx). This is a conservative amino acid change, resulting in the replacement of a nonpolar leucine with a nonpolar but sterically-constrained proline. The leucine at this location is conserved across species. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging” with a score of 0.999. In total this variant has not been seen in ~6500 individuals from publicly available population datasets. Not many of these controls are ancestry-matched with our patient, however. (Our patient has Mexican ancestry.) No variation at this codon is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals (as of 1/7/2013). No variation at this codon is present in dbSNP or in 1000 genomes. 1000 genomes contains 66 individuals of Mexican ancestry from Los Angeles, as of January 8, 2013. (Out of 1092 genotypes in phase 1, there are 66 people of Mexican ancestry from LA, 55 Puerto Ricans, 60 Colombians from Medellin, totaling 181 individuals.) GeneDx did not report controls.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.