Submissions for variant NM_001037.5(SCN1B):c.590C>T (p.Ala197Val)

gnomAD frequency: 0.00002  dbSNP: rs554201948

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000171054	SCV000223618	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28341588, 34038903, 34572065, 24324597, 34628405, 32192759, 29758173)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000646745	SCV000768530	uncertain significance	Brugada syndrome 5	2024-11-05	criteria provided, single submitter	clinical testing	The SCN1B gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001037.5, and corresponds to NM_199037.3:c.*5160C>T in the primary transcript. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 197 of the SCN1B protein (p.Ala197Val). This variant is present in population databases (rs554201948, gnomAD 0.006%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 29758173, 32192759). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects SCN1B function (PMID: 32192759). 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.
Ambry Genetics	RCV002354422	SCV002653272	uncertain significance	Cardiovascular phenotype	2023-10-27	criteria provided, single submitter	clinical testing	The p.A197V variant (also known as c.590C>T), located in coding exon 4 of the SCN1B gene, results from a C to T substitution at nucleotide position 590. The amino acid change results in alanine to valine at codon 197, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002478539	SCV002776891	uncertain significance	Generalized epilepsy with febrile seizures plus, type 1; Brugada syndrome 5; Atrial fibrillation, familial, 13; Developmental and epileptic encephalopathy, 52	2021-08-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535162	SCV004121275	uncertain significance	SCN1B-related disorder	2022-09-15	criteria provided, single submitter	clinical testing	The SCN1B c.590C>T variant is predicted to result in the amino acid substitution p.Ala197Val. This variant was reported in two individuals with Brugada syndrome or cardiac arrest (Gray et al. 2018. PubMed ID: 29758173; Wang et al. 2020. PubMed ID: 32192759; Zhu et al. 2021. PubMed ID: 34628405). Functional studies suggested that this variant could impact normal protein function (Wang et al. 2020. PubMed ID: 32192759; Zhu et al. 2021. PubMed ID: 34628405). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-35530162-C-T) and is interpreted as uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/190874/). A different nucleotide substitution affecting the same amino acid (p.Ala197Asp) has been reported in an individual with Brugada syndrome (Ricci et al. 2014. PubMed ID: 25253298). At this time, the clinical significance of the c.590C>T (p.Ala197Val) variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV000171054	SCV004145415	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	SCN1B: PM5, PP3
3billion, Medical Genetics	RCV004725020	SCV005329000	likely benign	Developmental and epileptic encephalopathy, 52	2024-09-20	criteria provided, single submitter	clinical testing	The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000171054	SCV001953868	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000171054	SCV001975818	uncertain significance	not provided		no assertion criteria provided	clinical testing