Submissions for variant NM_001130438.3(SPTAN1):c.131A>G (p.Tyr44Cys)

gnomAD frequency: 0.00002  dbSNP: rs368482631

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724442	SCV000227206	uncertain significance	not provided	2015-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000724442	SCV000492109	uncertain significance	not provided	2016-11-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SPTAN1 gene. The Y44C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y44C variant is observed in 0.01% alleles from individuals of European background, (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y44C variant is a non-conservative amino acid substitution, 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 position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, previously reported pathogenic variants in SPTAN1 include in-frame deletions or duplications located within the last four spectrin repeats of the protein, which are essential for dimerization (Saitsu et al., 2010), and the Y44C residue is outside this region. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000805848	SCV000945821	uncertain significance	Early infantile epileptic encephalopathy with suppression bursts	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 44 of the SPTAN1 protein (p.Tyr44Cys). This variant is present in population databases (rs368482631, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with SPTAN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 195127). 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 SPTAN1 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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV001729428	SCV001976922	uncertain significance	Developmental and epileptic encephalopathy, 5	2021-10-06	criteria provided, single submitter	clinical testing	PM2, PP3, BP1
Genome-Nilou Lab	RCV001729428	SCV002056736	uncertain significance	Developmental and epileptic encephalopathy, 5	2021-07-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000724442	SCV003822675	uncertain significance	not provided	2022-08-18	criteria provided, single submitter	clinical testing