Submissions for variant NM_001165963.4(SCN1A):c.2006C>T (p.Pro669Leu)

gnomAD frequency: 0.00001  dbSNP: rs570326929

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001132416	SCV001292076	uncertain significance	Generalized epilepsy with febrile seizures plus, type 2	2018-01-12	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	RCV001132417	SCV001292077	uncertain significance	Migraine, familial hemiplegic, 3	2018-01-12	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	RCV001245482	SCV001418773	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2023-09-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 669 of the SCN1A protein (p.Pro669Leu). This variant is present in population databases (rs570326929, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. This missense change has been observed in at least one individual who was not affected with SCN1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 893690). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN1A protein function. 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.
Lifecell International Pvt. Ltd	RCV001132416	SCV001712081	uncertain significance	Generalized epilepsy with febrile seizures plus, type 2		criteria provided, single submitter	clinical testing	A heterozygous missense variant (c.2006C>T) in exon 14 of the SCN1A gene that results in the amino acid substitution from Proline to Leucine at codon 669 (p.Pro669Leu) was identified. There is a moderate physicochemical difference between proline and leucine. The observed variant has a minor allele frequency of 0.0012% in gnomAD database and not reported in 1000 genome database. 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 5.52. 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). Missense Badness and MPC is 0.32 and 1.02 respectively. The 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. Based on the above evidence this variant has been classified as Variant of uncertain significance according to the ACMG guidelines.
GeneDx	RCV001759895	SCV001996314	uncertain significance	not provided	2024-05-21	criteria provided, single submitter	clinical testing	Identified in a patient with seizures in the published literature, however, familial segregation information and in vitro functional studies were not included (PMID: 37209046); This substitution is predicted to be in the cytoplasmic loop between the first and second homologous domains; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37209046)