ClinVar Genomic variation as it relates to human health

Converted during submission to Likely benign.

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 1.4% (5/344) Finnish chromosomes

Variant summary: SCN1B c.641G>A (p.Arg214Gln, also known as c.448+193G>A based on NM_001037) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0024 in 166160 control chromosomes, predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 420 fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN1B causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.641G>A has been reported in the literature in multiple individuals affected with Brugada syndrome, sudden infant death syndrome, and lone atrial fibrillation (Hu_2012, Crotti_2012, Holst_2012, Olesen_2012, Gray_2018, Husser_2017, Methner_2016, Ng_2013, Nunn_2016, Proost_2017, Ricci_2014). An internal sample reports the variant to co-occur with a likely pathogenic SCN5A variant, c.1338+2T>A. A function study, Hu_2012, indicates the variant decreases sodium current density. Authors have suggested the variant to be a functional polymorphism. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as twice as benign, four as likely benign, and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

SCN1B: BP4

This variant is associated with the following publications: (PMID: 22155598, 21994374, 22155597, 23465283, 22840528, 27711072, 28837624, 25253298, 23861362, 24055113, 22284586, 23414114, 28341588, 29758173, 29740331, 27435932, 31043699)

Criteria: BS1, BP4

The SCN1B c.641G>A, p.Arg214Gln variant (rs66876876) is reported in the literature in three individuals affected with atrial fibrillation (Husser 2017). This variant is also reported in ClinVar (Variation ID: 190847). This variant is found in the general population with an overall allele frequency of 0.2% (461/195480 alleles) in the Genome Aggregation Database. The arginine at codon 214 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.06). However, this missense variant may impact splicing by creating a novel cryptic acceptor splice site/weakening the nearby canonical splice site. Due to limited information, the clinical significance of the p.Arg214Gln variant is uncertain at this time. References: Husser et al. Rare variants in genes encoding the cardiac sodium channel and associated compounds and their impact on outcome of catheter ablation of atrial fibrillation. PLoS One. 2017 Aug 24;12(8):e0183690. PMID 28837624 Gene statement: Pathogenic variants in SCN1B are associated with autosomal dominant familial atrial fibrillation 13 (MIM: 615377), Brugada syndrome 5 (MIM: 612838), nonspecific cardiac conduction defect (MIM: 612838), generalized epilepsy with febrile seizures type 1 (MIM: 604233), and autosomal recessive early infantile epileptic encephalopathy 52 (MIM: 617350).

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg214Gln (c.641 G>A) in the SCN1B gene: The missense p.Arg214Gln variant has been previously reported in six unrelated individuals with BrS, all of whom are of European descent. Hu et al. reported it in two unrelated individuals of European descent with BrS and one child who died from SIDS (Hu et al, 2012) from a cohort of 476 (frequency 0.63%) patients with Brugada syndrome or SIDS. This variant was not seen in 476 ethnically matched controls with BrS, although Hu et al., (2012) did report that this variant had previously been seen in 4 of 807 (frequency 0.49%) ethnically matched controls in a separate dataset. Additionally, it was noted that each of these individuals also had one common polymorphism in the SCN1B gene (L210P, S248R and R250T). This variant was thought to interfere with sodium current density (Hu et al., 2012). This variant has also been reported in one Danish patient from a cohort of 42 (frequency 2.38%) Danish individuals with BrS (Holst et al., 2012). This affected individual did not have any other family members with BrS and segregation data was not available. The variant was absent in 216 ethnically similar controls in this study. This p.Arg214Gln variant has also been seen in a single patient from a cohort of 129 (frequency 0.77%) American and Italian patients with BrS (Crotti et al., 2012). It was seen in one individual in a cohort of 145 (frequency 0.69%) Italian patients with BrS (Ricci et al., 2014). Finally, this variant was seen in a single individual with BrS from a cohort of 22 (frequency 4.54%) Danish individuals with BrS (Oleson et al., 2012). It was not seen in 216 ethnically matched controls. p.Arg214Gln has also been seen in individuals with epilepsy and AF. It was reported in one patient with epilepsy out of a cohort of 360 (frequency 0.27%) American individuals with epilepsy (Patino et al., 2011). It was also seen in two individuals with AF in Denmark. This variant was not seen in 216 ethnically similar controls in this study (Oleson et al., 2012). The p.Arg214Gln variant results in a semi-conservative amino acid change from a positively charged Arginine to a polar Glutamine. The UCSC Genome Browser indicates that the Arginine amino acid is highly conserved from humans to primates. It is not conserved in all vertebrates. Glutamine is in fact the default amino acid in mice, rat & elephant. Additionally, the amino acids surrounding this Arginine are highly conserved through primates but not through all vertebrates. In silico analysis with Polyphen-2, SIFT and Mutation Taster are all consistent and predict this variant to be benign. In total, this variant has been seen in 27 out of ~5,200 controls (1,700 from published literature described above and 3,500 from NHLBI). The NHLBI Exome Sequencing Project dataset currently includes variant calls on 2,237 Caucasian and 1,241 African American individuals for this variant (as of 10/23/14). This variant was seen in a total of 21 European American individuals and 2 African American individuals (overall frequency 0.66%, Caucasian frequency almost 1%). There is no variation at this codon listed in 1000 genomes (as of 10/23/14). Variation at this codon is seen in the ExAC Browser dataset, which currently includes variant calls on 26,976 individuals of multiple ethnic backgrounds. It is particularly frequent among Caucasians. This variant was seen in a total of 87 individuals of Finnish(6), European(76), Latino(2), African(1) and South Asian(2) descent (frequency 0.33%) (as of 10/23/14).

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.