ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.3391G>A (p.Asp1131Asn)

gnomAD frequency: 0.00001  dbSNP: rs372555722
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Mayo Clinic Laboratories, Mayo Clinic RCV001354446 SCV001713205 uncertain significance not provided 2019-10-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001871921 SCV002242214 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2022-10-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1131 of the SCN1A protein (p.Asp1131Asn). This variant is present in population databases (rs372555722, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SCN1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1048975). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354446 SCV001549063 uncertain significance not provided no assertion criteria provided clinical testing The SCN1A p.Asp1103Asn variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs372555722) and was found in control databases in 3 of 251320 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: European (non-Finnish) in 3 of 113662 chromosomes (freq: 0.000026), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asp1103 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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