Submissions for variant NM_001165963.4(SCN1A):c.4556C>T (p.Pro1519Leu)

gnomAD frequency: 0.00004  dbSNP: rs372425457

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188964	SCV000242595	likely benign	not provided	2020-05-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29655203)
Ambry Genetics	RCV002317151	SCV000851744	benign	Inborn genetic diseases	2019-05-13	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001085148	SCV001015944	likely benign	Early infantile epileptic encephalopathy with suppression bursts	2023-03-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000986876	SCV001136024	benign	Severe myoclonic epilepsy in infancy	2023-08-22	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000986876	SCV001754758	uncertain significance	Severe myoclonic epilepsy in infancy		criteria provided, single submitter	clinical testing	A heterozygous missense variant (c.4556C>T) in exon 27 of the SCN1A gene that results in the amino acid substitution from Proline to Leucine at codon 1519 (p.pro1519Leu) was identified. There is a moderate physicochemical difference between Proline and Leucine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The observed variant is not present in the 1000 Genomes but it is present in the gnomAD databases with the minor allele frequency of 0.0033%. The reference base is conserved across the species and in-silico predictions by Polyphen and SIFT are damaging. The Missense Variants Z-Score for this variant is 5.23. Missense Variants Z-Score is produced by the Exome Aggregation Consortium (60,706 adult humans) by computing a signed Z score for the deviation of observed counts from the expected number. Positive Z scores indicate increased constraint (intolerance to variation) and therefore that the gene had fewer missense variants than expected. (DOI: 10.1038/nature19057). The Missense Badness Score and MPC value for this variant are 0.38 and 1.43, respectively. Missense Badness Score is the normalized fold difference of missense substitutions between observed and expected variants from ExAC dataset. This score is then combined with orthogonal deleteriousness metrics into one score called MPC (for Missense badness, PolyPhen-2, and Constraint) designed to classify whether a missense variants is deleterious. Variants with MPC ≥ 2 have a rate nearly 6 times higher in cases than in controls. While those with intermediate MPC values (1 ≤ MPC < 2) have a more modest excess in cases. This variant was found in ClinVar (Variant 206839) with a classification of Conflicting Interpretations of Pathogenicity and a review status of (1 star) criteria provided, conflicting interpretations. Based on the above evidence this variant has been classified as Variant of uncertain significance according to the ACMG guidelines.