ClinVar Miner

Submissions for variant NM_001037.5(SCN1B):c.373C>T (p.Arg125Cys)

gnomAD frequency: 0.00001  dbSNP: rs1135401736
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001565054 SCV001788324 likely pathogenic not provided 2022-11-22 criteria provided, single submitter clinical testing Published functional studies demonstrate decreased cell surface expression and decreased sodium current density in the homozygous state (Patino et al., 2009); Appeared to segregate with epilepsy in the heterozygous state in several members of a family previously tested at GeneDx, and also identified in the heterozygous state in unrelated individuals with febrile, focal, and generalized seizures tested at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27586289, 23934645, 26042039, 29307654, 24737232, 21040232, 23148524, 21463283, 28681755, 28927993, 28965169, 20375142, 23182416, 19710327)
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV001785611 SCV002028284 likely benign Seizure 2021-11-25 criteria provided, single submitter clinical testing inherited from healthy carrier
Labcorp Genetics (formerly Invitae), Labcorp RCV001865315 SCV002208942 uncertain significance Brugada syndrome 5 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 125 of the SCN1B protein (p.Arg125Cys). This variant is present in population databases (no rsID available, gnomAD 0.1%). This missense change has been observed in individuals with autosomal recessive SCN1B-related conditions (PMID: 19710327, 28681755). ClinVar contains an entry for this variant (Variation ID: 375686). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN1B function (PMID: 19710327). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224271 SCV003920422 likely pathogenic Generalized epilepsy with febrile seizures plus, type 1; Brugada syndrome 5; Atrial fibrillation, familial, 13; Developmental and epileptic encephalopathy, 52 2022-10-07 criteria provided, single submitter clinical testing This variant has been reported in the literature in the homozygous state in two individuals with epilepsy and other features suggestive of Dravet syndrome (Patino 2009 PMID: 19710327; Mukherjee 2017 PMID: 28681755). It has also been identified in the heterozygous state in two unrelated individuals with epilepsy at an external laboratory, segregating with disease in similarly affected family members in one family (GeneDx; ClinVar Variation ID: 375686); personal communication). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.007% [1/15280]; https://gnomad.broadinstitute.org/variant/19-35033664-C-T?dataset=gnomad_r3), and in ClinVar, with classifications ranging from likely pathogenic to likely benign (Variation ID: 375686). In vitro functional studies suggest that this variant impacts sodium channel activity and cell surface protein expression (Patino 2009 PMID: 19710327); however, these studies may not accurately represent in vivo biological function. Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Revvity Omics, Revvity RCV001565054 SCV004238634 likely pathogenic not provided 2023-11-20 criteria provided, single submitter clinical testing
Institute of Immunology and Genetics Kaiserslautern RCV000417191 SCV005382165 pathogenic Developmental and epileptic encephalopathy, 52 2023-02-28 criteria provided, single submitter clinical testing ACMG Criteria: PS3, PM2, PM5, PP3, PP5; Variant was found in homozygous state.
OMIM RCV000417191 SCV000502990 pathogenic Developmental and epileptic encephalopathy, 52 2020-10-09 no assertion criteria provided literature only

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