Submissions for variant NM_000335.5(SCN5A):c.5294T>A (p.Met1765Lys)

dbSNP: rs752476527

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183113	SCV000235523	uncertain significance	not provided	2016-11-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SCN5A gene. While the M1766K variant in the SCN5A gene has not been reported to our knowledge, a variant affecting this same residue, (M1766L) have been reported in association with LQTS (Valvidia et al., 2002). The M1766L variant was identified postmortem in a 16-month-old male with a clinical history suggestive of LQTS and was absent in the unaffected parents (Valvidia et al., 2002). The M1766K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, the M1766K variant is not observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server). Nonetheless, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183113	SCV001210326	uncertain significance	not provided	2024-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1766 of the SCN5A protein (p.Met1766Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 201534). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Met1766 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12123767). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199319	SCV001370400	uncertain significance	Sick sinus syndrome 1	2019-05-16	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3.