ClinVar Miner

Submissions for variant NM_001130438.3(SPTAN1):c.2221G>T (p.Ala741Ser)

gnomAD frequency: 0.00005  dbSNP: rs200241514
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189498 SCV000243141 uncertain significance not provided 2017-01-26 criteria provided, single submitter clinical testing p.Ala741Ser (GCC>TCC): c.2221 G>T in exon 17 of the SPTAN1 gene (NM_001130438.2) The A741S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports A741S was observed in 1/110 (0.9%) alleles from individuals of Puerto Rican background, indicating it may be a rare (benign) variant in this population. The A741S 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. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, previously reported pathogenic mutations 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 A741 residue is outside this region. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Invitae RCV000702357 SCV000831209 uncertain significance Early infantile epileptic encephalopathy with suppression bursts 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 741 of the SPTAN1 protein (p.Ala741Ser). This variant is present in population databases (rs200241514, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of SPTAN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 207325). 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.
Genome-Nilou Lab RCV001808511 SCV002056745 uncertain significance Developmental and epileptic encephalopathy, 5 2021-07-15 criteria provided, single submitter clinical testing

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