Submissions for variant NM_000335.5(SCN5A):c.5504T>C (p.Ile1835Thr)

gnomAD frequency: 0.00066  dbSNP: rs45563942

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058788	SCV000235619	uncertain significance	not provided	2023-08-04	criteria provided, single submitter	clinical testing	Reported in at least one proband with DCM and segregated with disease in affected relatives; of note, this variant was reported as I1835T due to alternate nomenclature (Hershberger et al., 2008; Cheng et al., 2010); Also identified in an infant with sudden unexplained death at three months of age, though no family history or segregation studies were described (Methner et al., 2016); 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: 15851227, 20129283, 24055113, 26332594, 25637381, 27896284, 25904541, 19841300, 27435932, 26746457, 19412328, 21167004)
Invitae	RCV000058788	SCV000557109	likely benign	not provided	2024-01-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621032	SCV000736441	likely benign	Cardiovascular phenotype	2019-09-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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 Diagnostics, LLC DBA Color Health	RCV001841554	SCV001354425	likely benign	Cardiac arrhythmia	2018-11-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
PreventionGenetics, part of Exact Sciences	RCV004541057	SCV004794982	likely benign	SCN5A-related disorder	2023-10-20	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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
Clinical Genetics, Academic Medical Center	RCV000058788	SCV001918884	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000058788	SCV001965205	likely benign	not provided		no assertion criteria provided	clinical testing