Submissions for variant NM_000335.5(SCN5A):c.680T>C (p.Leu227Pro)

gnomAD frequency: 0.00001  dbSNP: rs760011764

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182943	SCV000235339	likely pathogenic	not provided	2024-05-15	criteria provided, single submitter	clinical testing	Reported in a child with cardiomyopathy who harbored an additional pathogenic SCN5A variant on the opposite allele (in trans) (PMID: 32553838); Not observed at significant frequency in large population cohorts (gnomAD); 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: 30059973, Howard_Article_2022, 32553838, 28127136)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229800	SCV000291831	uncertain significance	Brugada syndrome	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 227 of the SCN5A protein (p.Leu227Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of SCN5A-related disease (PMID: 28127136, 30059973). 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. 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	RCV003278683	SCV004007601	uncertain significance	Cardiovascular phenotype	2023-06-09	criteria provided, single submitter	clinical testing	The p.L227P variant (also known as c.680T>C), located in coding exon 5 of the SCN5A gene, results from a T to C substitution at nucleotide position 680. The leucine at codon 227 is replaced by proline, an amino acid with similar properties. This variant has been detected in an individual reported to have Brugada syndrome pattern on ECG and sudden cardiac arrest (Switzer MP et al. Proc (Bayl Univ Med Cent), 2017 Jan;30:62-63). This variant co-occurred with another SCN5A variant in a pediatric case with cardiomyopathy (Freed AS et al. J Pediatr, 2020 Nov;226:202-212.e1). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000229800	SCV005423994	uncertain significance	Brugada syndrome	2024-04-30	criteria provided, single submitter	clinical testing
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.