ClinVar Genomic variation as it relates to human health

Variant summary: The SCN1B c.28G>A (p.Gly10Ser) variant involves the alteration of a non-conserved nucleotide, is not located in a known functional domain, and 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 16/5008 control chromosomes, predominantly observed in the African subpopulation (16/1322 African alleles from 1000G; 0.01210). This frequency is significantly greater than the estimated maximal expected allele frequency of a pathogenic SCN1B variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. However, the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site. The variant was identified in one SIDS case (also found in healthy African American adult control) and one LQTS patient without evidence of causality (i.e. co-segregation). In addition, one clinical diagnostic laboratory classified this variant as a VUS. Taken together and based on the allele frequency in the African subpopulation, this variant is classified as Likely Benign until additional information is available.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Reported in one African American infant with sudden infant death sydnrome (SIDS) and in one healthy, ethnically-matched control individual (Tan et al., 2010); Reported in one patient with LQTS (Rurio et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24662403, 20226894)

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.

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).