ClinVar Miner

Submissions for variant NM_018400.3(SCN3B):c.29T>C (p.Leu10Pro) (rs121918282)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171567 SCV000050611 uncertain significance Brugada syndrome 2018-04-05 criteria provided, single submitter research
GeneDx RCV000171069 SCV000223633 likely pathogenic not provided 2016-05-13 criteria provided, single submitter clinical testing The L10P likely pathogenic variant in the SCN3B gene has been reported previously in association with Brugada syndrome and atrial fibrillation, and was absent from approximately 1000 control alleles, collectively (Hu et al., 2009; Olesen et al., 2011; Le Scouarnec et al., 2015). Among a Danish cohort of 66 infants who died of SIDS, the L10P variant was identified in one and was absent from 208 control individuals (Winkle et al., 2015). Additionally, the L10P variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The L10P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is mostly conserved in mammals, however Proline 10 is present in one mammalian species. Nevertheless, functional studies have shown that the L10P mutation causes loss of transport and functional expression of SCN5A protein, leading to reduced sodium channel current (Hu et al., 2009; Olesen et al., 2011; Ishikawa et al., 2013). Therefore, this variant is likely pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000220802 SCV000272404 uncertain significance not specified 2015-01-23 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Leu10Pro vari ant in SCN3B has been reported in 1 individual with Brugada syndrome and 1 indiv idual with atrial fibrillation (Hu 2009, Olesen 2011, Olesen 2014). In addition, this variant has been identified in 19/66726 of European chromosomes by the Exo me Aggregation Consortium (ExAC,; dbSNP 12191828 2). In vitro functional studies provide some evidence that this variant may impa ct protein function (Hu 2009, Olesen 201), though these types of assays may not accurately represent biological function. Leucine (Leu) at position 10 is not co nserved in mammals with 3 mammals (gibbon, hedgehog, and shrew) carrying a proli ne (Pro) at this position, raising the possibility that this change may be toler ated. In summary, although the clinical significance of the p.Leu10Pro variant is uncertain it is less likely disease causing.
Ambry Genetics RCV000250087 SCV000319008 uncertain significance Cardiovascular phenotype 2020-03-11 criteria provided, single submitter clinical testing The p.L10P variant (also known as c.29T>C), located in coding exon 1 of the SCN3B gene, results from a T to C substitution at nucleotide position 29. The leucine at codon 10 is replaced by proline, an amino acid with similar properties. This alteration has been reported in individuals with Brugada syndrome, atrial fibrillation, long QT syndrome, and sudden infant death syndrome as well as in an exome cohort (Olesen MS et al. Cardiovasc. Res. 2011 Mar; 89(4):786-93; Dorschner MO et al. Am. J. Hum. Genet. 2013 Oct; 93(4):631-40; Ng D et al. Circ Cardiovasc Genet 2013 Aug; 6(4):337-46; Le Scouarnec S et al. Hum. Mol. Genet. 2015 May; 24(10):2757-63; Winkel BG et al. Heart Rhythm 2015 Jun; 12(6):1241-9). Functional studies suggest that the p.L10P alteration may impact protein trafficking and function; however, the mechanism of disease for SCN3B alterations is unclear (Hu D et al. Circ Cardiovasc Genet 2009 Jun; 2(3):270-8; Olesen MS et al. Cardiovasc. Res. 2011 Mar; 89(4):786-93; Ishikawa T et al. Circ. J. 2013 Dec; 77(4):959-67). This amino acid position is well conserved in available vertebrate species; however, proline is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000002574 SCV000883102 likely pathogenic Brugada syndrome 7 2018-11-21 criteria provided, single submitter clinical testing
Invitae RCV000002574 SCV000959538 uncertain significance Brugada syndrome 7 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 10 of the SCN3B protein (p.Leu10Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs121918282, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in several individuals affected with clinical features of SCN3B-related conditions (PMID: 20031595, 25650408, 22284586, 29247119, 21051419, 25757662, 31043699). ClinVar contains an entry for this variant (Variation ID: 2470). This variant has been reported to affect SCN3B protein function (PMID: 20031595, 21051419, 23257389). 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 RCV000002574 SCV000022732 pathogenic Brugada syndrome 7 2011-03-01 no assertion criteria provided literature only
OMIM RCV000128811 SCV000172469 pathogenic Atrial fibrillation, familial, 16 2011-03-01 no assertion criteria provided literature only
GeneReviews RCV000002574 SCV000188925 pathogenic Brugada syndrome 7 2014-04-10 no assertion criteria provided literature only

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