ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.5504T>C (p.Ile1835Thr) (rs45563942)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212993 SCV000235619 likely benign not specified 2017-11-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001084744 SCV000557109 likely benign Brugada syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621032 SCV000736441 likely benign Cardiovascular phenotype 2019-09-24 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;Other data supporting benign classification
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000058788 SCV000884489 likely benign not provided 2018-03-20 criteria provided, single submitter clinical testing The SCN5A c.5507T>C; p.Ile1836Thr variant (rs45563942, ClinVar variant ID 39445) has been reported to segregate with dilated cardiomyopathy in one family (Hershberger 2008), but was also detected in a healthy control individual (Kapa 2009), and several subsequent studies have concluded that the frequency of this variant in the population is inconsistent with a causative role in disease (Amendola 2015, Dorschner 2013, Nourhavesh 2016, Olfson 2015). This variant is listed in the genome Aggregation Database (gnomAD) with an African population frequency of 0.3% (identified on 73 out of 24,028 chromosomes). The isoleucine at position 1836 is highly conserved, considering 9 species, and computational analyses of the effects of the p.Ile1836Thr variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: possibly damaging). Based on the available information, the p.Ile1836Thr variant is likely to be benign.
Color RCV001187580 SCV001354425 likely benign Arrhythmia 2018-11-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212993 SCV001426797 likely benign not specified 2020-07-13 criteria provided, single submitter clinical testing Variant summary: SCN5A c.5507T>C (p.Ile1836Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 249380 control chromosomes, predominantly at a frequency of 0.0033 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 132-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN5A causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.5507T>C was reported to co-segregate with cardiomyopathy in one African-American family (Hershberger_2008, Cheng_2010) but was also subsequently reported by different studies in multiple individuals without a cardiomyopathy phenotype (e.g. Kapplinger_2015, VanDriest_2016). Furthermore, experimental evidence demonstrated that expression of the variant alone in HEK293 cells did not cause any significant changes in biophysical properties compared to wild-type (Cheng_2010). A co-occurrence with a pathogenic variant has been reported (TTR c.424G>A, p.Val142Ile; Internal testing). Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
OMIM RCV000032640 SCV000056403 pathogenic Dilated cardiomyopathy 1E 2008-05-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058788 SCV000090308 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:19841300;PMID:20129283;PMID:19412328).
CSER _CC_NCGL, University of Washington RCV000148847 SCV000190590 uncertain significance Primary dilated cardiomyopathy 2014-06-01 no assertion criteria provided research

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