ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.3521C>G (p.Thr1174Ser)

gnomAD frequency: 0.00159  dbSNP: rs121918799
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000723551 SCV000111456 uncertain significance not provided 2017-12-27 criteria provided, single submitter clinical testing
GeneDx RCV000723551 SCV000242545 benign not provided 2019-05-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24842605, 24679980, 22780858, 25576396, 24664660, 23801004, 23398611, 11254445, 22550089, 18021921, 21396429, 26990884, 27017028, 26763045, 26236192, 20301562, 31782251, 31765958)
Genetic Services Laboratory,University of Chicago RCV000188915 SCV000248793 likely benign not specified 2020-10-12 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000296106 SCV000417785 likely benign Epilepsy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000059493 SCV000417786 likely benign Migraine, familial hemiplegic, 3 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415355 SCV000492946 uncertain significance Seizure; Generalized tonic-clonic seizures; Generalized non-motor (absence) seizure 2014-11-13 criteria provided, single submitter clinical testing
Invitae RCV001082811 SCV000633848 benign Early infantile epileptic encephalopathy with suppression bursts 2021-12-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000718099 SCV000848961 likely benign History of neurodevelopmental disorder 2018-07-17 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Mendelics RCV000986890 SCV001136040 uncertain significance Severe myoclonic epilepsy in infancy 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001129578 SCV001289115 likely benign Generalized epilepsy with febrile seizures plus, type 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000059493 SCV001369478 uncertain significance Migraine, familial hemiplegic, 3 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV001129578 SCV001428982 benign Generalized epilepsy with febrile seizures plus, type 2 2022-04-26 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000723551 SCV002496545 benign not provided 2022-03-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000188915 SCV002548155 benign not specified 2022-05-05 criteria provided, single submitter clinical testing Variant summary: SCN1A c.3521C>G (p.Thr1174Ser) results in a conservative amino acid change located in the Sodium ion transport-associated domain (IPR010526) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251678 control chromosomes (gnomAD, Escayg_2001, Yordanova_2011, Cestele_2013), predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 150-fold of the estimated maximal expected allele frequency for a pathogenic variant in SCN1A causing SCN1A-Related Seizure Disorder phenotype (1.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3521C>G has been reported in the literature but evidence does not allow for unequivocal conclusions regarding association of the variant with disease. Specifically, the variant was found to segregate with SCN1A-Related Seizure Disorder in some families (e.g. Cestele_2013, Lal_2016), while in other families it was found in affected probands who had inherited it from their unaffected parents or in families with some affected and some unaffected carriers (e.g. Yordanova_2011, LeGal_2014, Lal_2016, Till_2020). In addition, co-occurring pathogenic variants have been reported in multiple affected individuals (SCN1A c.3637C>T, p.Arg1213X; GRIN2B c.1619G>A, p.R540H; SCN1A c.4219C>T, p.Arg1407X; SCN1A c.3677delT, p.Phe1226SerfsX2) (Internal testing, Lal_2016, Till_2020), providing supporting evidence for a benign role. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (INaP), consistent with gain of function (Cestele_2013). However, it is uncertain to what extent and if these findings correlate with actual disease manifestation. Twelve ClinVar submitters have assessed the variant since 2014: eight classified the variant as benign/likely benign, three as of uncertain significance and one as pathogenic. Based on the evidence outlined above, the variant was classified as benign.
UniProtKB/Swiss-Prot RCV000059493 SCV000091019 not provided Migraine, familial hemiplegic, 3 no assertion provided not provided
Bioinformatics Core,Luxembourg Center for Systems Biomedicine RCV000655982 SCV000588258 pathogenic Childhood epilepsy with centrotemporal spikes 2017-01-01 no assertion criteria provided case-control CAADphred>15

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