ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs372425457
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Total submissions: 5
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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 RCV000720860 SCV000851744 benign History of neurodevelopmental disorder 2019-05-13 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Invitae RCV001085148 SCV001015944 likely benign Early infantile epileptic encephalopathy with suppression bursts 2021-10-16 criteria provided, single submitter clinical testing
Mendelics RCV000986876 SCV001136024 uncertain significance Severe myoclonic epilepsy in infancy 2019-05-28 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.

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