ClinVar Miner

Submissions for variant NM_001037.5(SCN1B):c.448+354G>A

gnomAD frequency: 0.00001  dbSNP: rs752552401
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000171063 SCV000223627 uncertain significance not provided 2018-11-05 criteria provided, single submitter clinical testing p.V268I:GTT>ATT; c.802 G>A. A heterozygous G>A nucleotide substitution was identified in exon 3 of the SCN1B gene, resulting in the replacement of the normal Valine codon (GTT) with an Isoleucine codon (ATT) at amino acid position 268 in the beta subunit of the voltage-gated sodium channel type 1 (SCN1B). This sequence change is denoted Val268Ile (aka V268I) at the protein level and c.802 G>A at the cDNA level. The Val268Ile variant in the SCN1B gene has not been previously published as a disease-causing mutation or as a benign polymorphism, to our knowledge. Val268Ile results in a conservative amino acid substitution at the last amino acid residue of the SCN1B protein, which is not conserved across species throughout evolution. However, this variant occurs in an alternate transcript of the SCN1B gene, where at least one other mutation has been reported in association with Brugada syndrome. Furthermore, Val268Ile was not observed in up to 600 alleles from control individuals of Caucasian and African American ancestry tested at GeneDx indicating it is likely not a common, benign variant in these populations. The variant is found in BRUGADA panel(s).
Invitae RCV001361072 SCV001557033 uncertain significance Brugada syndrome 5 2022-11-28 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SCN1B function (PMID: 29572929). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 190882). This missense change has been observed in individual(s) with sudden infant death syndrome (PMID: 29572929). This variant is present in population databases (rs752552401, gnomAD 0.05%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 268 of the SCN1B protein (p.Val268Ile).

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