Submissions for variant NM_000335.5(SCN5A):c.3688G>A (p.Glu1230Lys)

gnomAD frequency: 0.00001  dbSNP: rs199473598

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183184	SCV000235601	pathogenic	not provided	2011-11-11	criteria provided, single submitter	clinical testing	p.Glu1231Lys in the SCN5A gene; disease-causing mutation (Tester D et al. 2008). TheG>A nucleotide substitution in exon 21 of the SCN5A gene, results in replacement of the normal Glutamic acid codon (GAG) with a Lysine codon (AAG) at amino acid position 1231 in the cardiac sodium voltage-gated channel, type V-a. This missense change is denoted p.Glu1231Lys (aka E1231K) at the protein level and c.3691 G>A at the cDNA level. The Glu1231Lys mutation has been reported in association with LQTS (Tester D et al. 2008). Tester et al. reported Glu1231Lys in one patient with LQTS and did not observe it in more than 1,500 control alleles. This mutation also was not observed in up to 400 control alleles from individuals of African American and Caucasian ancestry tested at GeneDx, indicating it is not a common benign polymorphsim. Glu1231Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine residue at a position that is class conserved. Furthermore, mutations in surrounding codons (Tyr1228His, Arg1232Gln, Lys1236Arg, Lys1236Asn, Leu1239Pro) have been reported in association with Brugada syndrome, further supporting the functional importance of this region of the protein. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183184	SCV000937530	uncertain significance	not provided	2022-12-06	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (Invitae). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 67812). This variant is present in population databases (rs199473598, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1231 of the SCN5A protein (p.Glu1231Lys).
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058587	SCV000090107	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:15840476). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.