ClinVar

Description

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. Seen in a patient in our center with severe sinus node dysfunction of unclear etiology, with additional conduction system disease. The patient carried another rare variant in SCN5A and a rare variant in MYH7. p.Met1793Lys (M1793K; c.5378 T>A) in the SCN5A gene This variant is completely novel, and has not been previously reported as a disease-causing mutation or as a benign polymorphism according to the testing report and to our own searches of PubMed and Google. Variation at nearby residues (within 10 amino acids) has been reported in association with disease, supporting the functional importance of this region of the protein (according to UniProtKB and IRCCS Fondazione Salvatore Maugeri database): E1784K with LQT3 and Brugada (in vitro data available), S1787N with LQT3, D1790G with LQT3 (in HGMD via GeneDx), D1792N with sick sinus syndrome (in HGMD via GeneDx), Y1795C with LQT3 (in vitro data available; in HGMD via GeneDx), Y1795H with Brugada (in vitro data available; in HGMD via GeneDx), Y1795D in LQT3 and Brugada (in vitro data available). This is a non-conservative amino acid change, resulting in the replacement of a nonpolar methionine with a basic, positively-charged lysine. The methionine at this location is conserved across species, according to GeneDx. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “benign” with a score of 0.419. (GeneDx says its analysis predicts it to be damaging.) In total this variant has not been seen in ~6500 individuals from published controls and 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.