ClinVar Miner

Submissions for variant NM_001378969.1(KCND3):c.677TCT[1] (p.Phe227del)

dbSNP: rs397515475
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268494 SCV001447465 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris RCV000056298 SCV001519149 pathogenic Spinocerebellar ataxia type 19/22 2021-01-04 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000056298 SCV002555876 pathogenic Spinocerebellar ataxia type 19/22 2022-06-14 criteria provided, single submitter clinical testing Variant summary: KCND3 c.680_682delTCT (p.Phe227del) results in an in-frame deletion that is predicted to remove one amino acid from the Ion transport domain (IPR005821) of the encoded protein. The variant was absent in 250304 control chromosomes. c.680_682delTCT has been reported in the literature to cosegregate with disease in multiple individuals from two independent well genotyped families affected with Spinocerebellar Ataxia Type 22, which overlaps with the locus of Spinocerebellar Ataxia Type 19 (example, Lee_2012). It has also been reported among pathogenic variants identified in at-least one individual within a cohort of individuals undergoing next-generation sequencing (NGS) analysis for Herediatry Ataxia's (example, Galatolo_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Lee_2012). The most pronounced variant effect results in low current densities by electrophysiological recordings and intracellular retention, suggesting that p.F227del causes a loss of channel function by interfering with proper plasma membrane targeting and incorporation into a functional tetrameric channel complex. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Athena Diagnostics RCV001268494 SCV005622635 pathogenic not provided 2024-01-09 criteria provided, single submitter clinical testing This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23280837, 25854634)
OMIM RCV000056298 SCV000087467 pathogenic Spinocerebellar ataxia type 19/22 2012-12-01 no assertion criteria provided literature only

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