ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4855A>G (p.Met1619Val) (rs373967247)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188980 SCV000242611 uncertain significance not specified 2014-09-12 criteria provided, single submitter clinical testing Met1619Val (ATG>GTG): c.4855 A>G in exon 26 in the SCN1A gene (NM_001165963.1). The M1619V variant in the SCN1A gene was reported previously in an indivdiual with intractable epilepsy (Wang et al., 2012). The M1619V variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M1619V variant is a conservative amino acid substitution, which occurs at a position that is overall conserved in mammals, although Valine is observed in a few lower vertebrates. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense mutations in nearby residues (V1611F; V1612I; I1616T) have been reported in association with SCN1A-related disorders, supporting the functional importance of this region of the protein. We interpret M1619V as a variant of unknown significance. The variant is found in EPILEPSY,INFANT-EPI panel(s).
Invitae RCV000463438 SCV000559703 benign not provided 2018-09-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000188980 SCV000918183 benign not specified 2018-08-29 criteria provided, single submitter clinical testing Variant summary: SCN1A c.4855A>G (p.Met1619Val) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 245532 control chromosomes, predominantly within the South Asian subpopulation in the gnomAD database at a frequency of 0.004, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 320-fold above the estimated maximal expected allele frequency for a pathogenic variant in SCN1A causing Intractable Childhood Epilepsy with Generalized Tonic-Clonic seizures phenotype (1.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.4855A>G, has been reported in the literature in one individual affected with Intractable Childhood Epilepsy (Wang_2012). This report does not provide unequivocal conclusions about association of the variant with Intractable Childhood Epilepsy with Generalized Tonic-Clonic seizures. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000986873 SCV001136020 uncertain significance Severe myoclonic epilepsy in infancy 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001521140 SCV001730413 benign Early infantile epileptic encephalopathy with suppression bursts 2020-09-15 criteria provided, single submitter clinical testing

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