ClinVar Miner

Submissions for variant NM_001037.5(SCN1B):c.448+88G>A (rs267607028)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000171062 SCV000223626 pathogenic not provided 2011-11-07 criteria provided, single submitter clinical testing This nonsense change is denoted Trp179Stop (aka W179X) at the protein level and c.536 G>A at the cDNA level. A G>A nucleotide substitution was identified in exon 3A of the SCN1B gene (alternative transcript variant B), resulting in replacement of the normal Tryptophan codon (TGG) with a Stop codon (TAG) at amino acid position 179 in the beta subunit of voltage-gated sodium channel type 1. The Trp179Stop mutation in the SCN1B gene has been reported previously in association with Brugada syndrome and this mutation was absent from 1,404 control individuals from various ethnic backgrounds (Watanabe et al, 2008). Watanabe et al. (2008) identified the Trp179Stop mutation in 53 year-old male with Brugada syndrome, as well as in two family members with cardiac conduction abnormalities (Watanabe et al, 2008). Functional studies reported that while co-expression of Na(v)1.5 with wild type beta-1B increases sodium current density, the Trp179Stop mutant beta-1B did not modulate Na(v)1.5 sodium current (Watanabe et al, 2008). Trp179Stop is predicted to cause loss of normal protein function due to production of an abnormal, prematurely truncated protein lacking the transmembrane and cytoplasmic domains needed to integrate into the sarcolemma and associate with Na(v)1.5 (Watanabe et al, 2008). The variant is found in BRUGADA panel(s).
Invitae RCV000009836 SCV000959398 uncertain significance Brugada syndrome 5 2018-09-14 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SCN1B gene (p.Trp179*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acids of the SCN1B protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families with Brugada syndrome, sudden arrythmic death syndrome and progressive familial heart block type 1 (PMID: 18464934, 28449774, 22247482). ClinVar contains an entry for this variant (Variation ID: 9254). Experimental studies have shown that this missense change failed to increase NaV1.5 current and did not modulate the effect of the WT β1B protein.(PMID: 18464934). 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.
OMIM RCV000009836 SCV000030057 pathogenic Brugada syndrome 5 2008-06-01 no assertion criteria provided literature only

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