ClinVar Miner

Submissions for variant NM_001130438.3(SPTAN1):c.7121C>G (p.Pro2374Arg) (rs796053330)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189536 SCV000243179 uncertain significance not provided 2013-03-26 criteria provided, single submitter clinical testing p.Pro2374Arg (CCT>CGT): c.7121 C>G in exon 55 of the SPTAN1 gene (NM_001130438.1) The Pro2374Arg missense change 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 or among the various ethnic groups studied in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as an uncharged, non-polar Proline residue is replaced by a positively charged, Arginine residue and the gain of a Proline may affect the secondary structure of the protein. Pro2374Arg alters a conserved position in the alpha-II spectrin protein and multiple in-silico algorithms predict it may be damaging to the structure/function of the protein. However, previously reported pathogenic mutations in SPTAN1 are located within the last four spectrin repeats that are essential for dimerization (Saitsu et al., 2010), and the Pro2374 residue is outside this region. Alternatively, the c.7121 C>G nucleotide substitution may be a splice site mutation as it results in the gain of a cryptic donor splice site within exon 55 of the SPTAN1 gene. Two in silico splice algorithms predict this substitution functions worse than the natural donor splice site and result in abnormal gene splicing while another algorithms predict it has no effect. However, the actual effect of the c.7121 C>G sequence change in vivo is unknown in the absence of RNA studies. The variant is found in EPILEPSY panel(s).

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