ClinVar Miner

Submissions for variant NM_001037.5(SCN1B):c.448+45G>A

gnomAD frequency: 0.00001  dbSNP: rs762453360
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000171043 SCV000223607 uncertain significance not provided 2013-03-16 criteria provided, single submitter clinical testing p.Ala165Thr (GCC>ACC): c.493 G>A in exon 3 of the SCN1B gene (NM_199037.2). The Ala165Thr missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project or among the various ethnic groups studied in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative, as a non-polar Alanine residue is replaced by a polar Threonine residue. However, it alters a poorly conserved position in the protein, and it alters a position in an alternative transcript of the gene (NM_199037.2). One in silico algorithm suggests Ala165Thr may possibly be damaging to protein structure/function while another model predicts it may be benign. Therefore, based on the currently available information, it is unclear whether Ala165Thr is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000702088 SCV000830922 uncertain significance Brugada syndrome 5 2023-11-13 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 165 of the SCN1B protein (p.Ala165Thr). This variant is present in population databases (rs762453360, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SCN1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 190863). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

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