Submissions for variant NM_001330260.2(SCN8A):c.4441A>G (p.Met1481Val)

dbSNP: rs886041670

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000338932	SCV000330389	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26029160)
Invitae	RCV000636327	SCV000757766	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2022-02-24	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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 280470). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1481 of the SCN8A protein (p.Met1481Val).
CeGaT Center for Human Genetics Tuebingen	RCV000338932	SCV002063044	uncertain significance	not provided	2021-10-01	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001254990	SCV001431078	likely pathogenic	Focal impaired awareness seizure	2020-01-10	no assertion criteria provided	clinical testing	The heterozygous missense p.Met1481Val variant is absent from the gnomAD database. The variant has been submitted to the ClinVar database by other genetic testing laboratories, including one instance where a laboratory has reported this variant as confirmed de novo in a patient with seizures [Variation ID: 280470]. Most of the SCN8A pathogenic variants reported to-date are missense and de novo [NBK379665; PMID: 25568300]. The p.Met1481Val variant is predicted deleterious by multiple in silico prediction tools. The affected residue is evolutionarily conserved and is predicted to be located in the cytoplasmic loop between the third and fourth homologous repeat domains [PMID: 26029160]. Based on available evidence along with the observation that the proband has inherited this variant from her affected mother, the p.Met1481Val variant in the SCN8A gene is assessed as likely pathogenic.