Submissions for variant NM_001165963.4(SCN1A):c.4972A>C (p.Thr1658Pro)

dbSNP: rs1064794766

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482880	SCV000569902	likely pathogenic	not provided	2017-02-07	criteria provided, single submitter	clinical testing	A novel T1658P variant that is likely pathogenic has been identified in the SCN1A gene. TheT1658P variant has not been published as a pathogenic variant, nor has it been reported as abenign variant to our knowledge. It was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it isnot a common benign variant in these populations. The T1658P variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residuesdiffer in polarity, charge, size and/or other properties. This substitution occurs at a conservedposition predicted to be within the intracellular loop between the S4 and S5 transmembranesegments of the fourth homologous domain of the SCN1A protein. Different missense variants inthe same residue (T1658M, T1658R) as well as multiple missense variants in nearby residues havebeen reported in the Human Gene Mutation Database in association with SCN1A-relateddisorders (Stenson et al., 2014), supporting the functional importance of this region of the protein.In silico analysis predicts this variant is probably damaging to the protein structure/function.Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot beexcluded.
Lifecell International Pvt. Ltd	RCV003221302	SCV003914819	likely pathogenic	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.4972A>C in Exon 29 of the SCN1A gene that results in the amino acid substitution p.Thr1658Pro was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic [Variation ID: 420883]. A different missense mutation [p.Thr1658Lys] has been reported previously in patients affected with Dravet Syndrome (Sahli M, et.al., 2019). For these reasons, this variant has been classified as Likely Pathogenic.