ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.4612G>A (p.Val1538Ile) (rs780360360)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587898 SCV000697768 uncertain significance not provided 2016-01-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000720435 SCV000851312 uncertain significance History of neurodevelopmental disorder 2016-10-26 criteria provided, single submitter clinical testing The p.V1538I variant (also known as c.4612G>A), located in coding exon 25 of the SCN1A gene, results from a G to A substitution at nucleotide position 4612. The valine at codon 1538 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in an individual with late onset Dravet syndrome and an individual with isolated autism spectrum disorder (ASD) (Depienne C et al. J. Med. Genet., 2009 Mar;46:183-91; Koshimizu E et al. PLoS ONE, 2013 Sep;8:e74167). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is well conserved in available 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 alteration remains unclear.
Fulgent Genetics,Fulgent Genetics RCV000764285 SCV000895304 uncertain significance Familial hemiplegic migraine type 3; Severe myoclonic epilepsy in infancy; Generalized epilepsy with febrile seizures plus, type 2 2018-10-31 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001262414 SCV001440276 uncertain significance Generalized epilepsy with febrile seizures plus, type 2 2019-01-01 criteria provided, single submitter clinical testing
Invitae RCV001337164 SCV001530754 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2020-08-14 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1538 of the SCN1A protein (p.Val1538Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs780360360, ExAC 0.005%). This variant has been observed in individual(s) with Dravet syndrome or autism spectrum disorder (PMID: 18930999, 24066114). ClinVar contains an entry for this variant (Variation ID: 496120). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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