Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Rady Children's Institute for Genomic Medicine, |
RCV001731285 | SCV001984848 | pathogenic | Episodic ataxia/myokymia syndrome | 2020-06-22 | criteria provided, single submitter | clinical testing | This variant has been previously reported in patients with episodic ataxia and myokymia as a de novo heterozygous change (PMID: 26395884), and as inherited in cases with multiple similarly affected family members (PMID: 10355668, 10414318, 19779067). The clinical presentations of individuals with the p.Thr226Arg is highly variable and has included complex partial epilepsy and apneic events in infancy (PMID: 10355668). Functional studies suggest the p.Thr226Arg exerts a dominant negative effect on potassium channel function and may impair neuronal repolarization (PMID: 10355668, 10414318, 11773313). An in-vitro study of this variant in rat neurons detected no effect on neuronal excitability; however, it identified increased neurotransmitter release (PMID: 19779067). Other pathogenic variants have been observed at this amino acid residue including p.Thr226Met (PMID: 8871592) and p.Thr226Lys (PMID: 17136396, 22965560). The c.677C>G (p.Thr226Arg) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.677C>G (p.Thr226Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.677C>G (p.Thr226Arg) variant is classified as Pathogenic. |
| Gene |
RCV001785451 | SCV002028123 | pathogenic | not provided | 2021-11-16 | criteria provided, single submitter | clinical testing | Functional studies indicated that T226R results in a decrease in voltage activated current and cause a dominant negative effect on potassium channel function (Zuberi et al., 1999; Spauschus et al., 1999); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17395136, 11773313, 10414318, 19779067, 11026449, 15351427, 10355668, 26395884) |
| OMIM | RCV000014436 | SCV000034685 | pathogenic | Episodic ataxia type 1 | 1999-05-01 | no assertion criteria provided | literature only | |
| Gene |
RCV000014436 | SCV000040559 | not provided | Episodic ataxia type 1 | no assertion provided | literature only |