ClinVar Miner

Submissions for variant NM_001165963.4(SCN1A):c.3968C>A (p.Pro1323His)

dbSNP: rs1057521746
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000430833 SCV000524399 likely pathogenic not provided 2016-02-25 criteria provided, single submitter clinical testing A published P1323H variant that is likely pathogenic has been identified in the SCN1A gene. TheP1323H variant has been reported previously as a de novo variant in an individual with Dravetsyndrome (Specchio et al., 2014). It was not observed in approximately 6,500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not acommon benign variant in these populations. The P1323H variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a conserved position predicted to bewithin the voltage-sensor transmembrane segment S4 of the third homologous domain of the SCN1Aprotein. Different missense variants at the same position (P1323R, P1323S) as well as multiplemissense variants in nearby residues have been reported in association with SCN1A-related disorders(Stenson et al., 2014; SCN1A Variant Database), supporting the functional importance of this regionof the protein. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. Therefore, this variant is likely pathogenic; however, the possibility that it isbenign cannot be excluded.
Ambry Genetics RCV002318436 SCV000850921 likely pathogenic Inborn genetic diseases 2017-04-28 criteria provided, single submitter clinical testing The p.P1323H variant (also known as c.3968C>A), located in coding exon 20 of the SCN1A gene, results from a C to A substitution at nucleotide position 3968. The proline at codon 1323 is replaced by histidine, an amino acid with similar properties. In one case study, this variant was confirmed to be de novo in a 2-year-old with suspected Dravet syndrome, whose history included a hemiconvulsive febrile seizure at 6 months of age, generalized afebrile seizures at 9 months, and an occipital seizure (induced by intermittent photo stimulation) at 11 months (Specchio N et al. Seizure, 2014 Apr;23:309-13). This variant is located in the S4 transmembrane region and is predicted to be structurally deleterious (Wu J et al. Science, 2015 Dec;350). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV002525370 SCV003301876 pathogenic Early infantile epileptic encephalopathy with suppression bursts 2022-02-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro1323 (also known as p.Pro1312) amino acid residue in SCN1A. Other variant(s) that disrupt this residue have been observed in individuals with SCN1A-related conditions (PMID: 21868258, 31009440), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 383819). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 24472396). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 1323 of the SCN1A protein (p.Pro1323His).

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