ClinVar Miner

Submissions for variant NM_000335.5(SCN5A):c.5901C>G (p.Ile1967Met) (rs199473333)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000058816 SCV000055296 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154831 SCV000204513 uncertain significance not specified 2013-04-12 criteria provided, single submitter clinical testing The Ile1968Met variant in SCN5A has not been reported in individuals with arrhyt hmias or previously identified by our laboratory, but has been identified in 1 A frican American control chromosome from over 2600 controls tested (Ackerman 2004 , Kapa 2009, Kapplinger 2010). In addition, this variant has been identified in 1/4120 African American chromosomes from a broad population by the NHLBI Exome S equencing Project (http://evs.gs.washington.edu/EVS/) and in 1/566 European chro mosomes by the ClinSeq Project (dbSNP rs199473333). Computational analyses (bioc hemical amino acid properties, conservation, AlignGVGD, and PolyPhen2) suggest t hat this variant may not impact the protein, though this information is not pred ictive enough to rule out pathogenicity. In summary, additional studies are need to fully assess the clinical significance of this variant.
GeneDx RCV000058816 SCV000235554 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing The I1968M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The I1968M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, in silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, the I1968M variant was identified in 1/2,760 control alleles in a study by Kapa et al. (Kapa et al., 2009). However, the I1968M variant was not observed with any significant frequency in approximately 4,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution also occurs at a position that is class conserved in mammals. Furthermore, a mutation at the same codon (I1968S) was identified in a 41-year-old female with Brugada syndrome (Frustaci et al., 2005). Histology revealed right and left ventricular cardiomyopathic changes and functional studies showed impacts on inward sodium current suggesting that I1968S causes a cardiac ion channel abnormality which may lead to cell degeneration and death (Frustaci et al., 2005). Other missense mutations in nearby residues (K1958Q, S1964F, Y1977N) have been reported in association with Brugada syndrome or long QT syndrome, supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s).
Invitae RCV000535115 SCV000637195 uncertain significance Brugada syndrome 2020-10-24 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 1968 of the SCN5A protein (p.Ile1968Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs199473333, ExAC 0.03%). It has been reported in two healthy controls (PMID: 25904541). ClinVar contains an entry for this variant (Variation ID: 68018). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics,Fulgent Genetics RCV000764499 SCV000895570 uncertain significance Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1, autosomal recessive; Progressive familial heart block, type 1A; Paroxysmal familial ventricular fibrillation 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000154831 SCV000920194 uncertain significance not specified 2017-10-23 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.5904C>G (p.Ile1968Met) variant is causing a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 18/275108 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000667 (16/23990). This frequency is about 7 times the estimated maximal expected allele frequency of a pathogenic SCN5A variant (0.0001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, until more definitive clinical and functional studies become available.
Color Health, Inc RCV001184481 SCV001350455 likely benign Arrhythmia 2020-08-09 criteria provided, single submitter clinical testing
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058816 SCV000090336 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:19841300;PMID:20129283).

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