Submissions for variant NM_001165963.4(SCN1A):c.3044C>T (p.Ala1015Val)

gnomAD frequency: 0.00002  dbSNP: rs772487501

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189086	SCV000242717	uncertain significance	not provided	2015-11-30	criteria provided, single submitter	clinical testing	p.Ala1015Val (GCT>GTT): c.3044 C>T in exon 16 of the SCN1A gene (NM_001165963.1) A variant of unknown significance has been identified in the SCN1A gene. The A1015V variant was previously identified in an individual with severe myoclonic epilepsy of infancy (Dravet syndrome); however, parental studies were not reported. It was not observed 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. This substitution alters a conserved position in the cytoplasmic loop between the second and third homologous domains of the SCN1A protein (Escayg et al., 2010), and multiple missense mutations have been reported in this region of the protein in association with SCN1A-related disorders in an external mutation database, supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the A1015V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Illumina Laboratory Services, Illumina	RCV001132322	SCV001291981	uncertain significance	Migraine, familial hemiplegic, 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001133243	SCV001292937	uncertain significance	Generalized epilepsy with febrile seizures plus, type 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001205593	SCV001376857	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2019-10-09	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 206939). This variant is present in population databases (rs772487501, ExAC 0.03%). This sequence change replaces alanine with valine at codon 1015 of the SCN1A protein (p.Ala1015Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine.