Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Blueprint Genetics | RCV000208485 | SCV000263968 | likely benign | not specified | 2014-12-11 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000249346 | SCV000320287 | likely benign | Cardiovascular phenotype | 2023-12-07 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
Labcorp Genetics |
RCV000558965 | SCV000640063 | uncertain significance | Spinocerebellar ataxia type 19/22 | 2024-01-13 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 214 of the KCND3 protein (p.Lys214Arg). This variant is present in population databases (rs142744204, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with atrial fibrillation, an episodic gait disorder or Brugada syndrome (PMID: 21349352, 22402074, 25410959, 26220970, 29482223). ClinVar contains an entry for this variant (Variation ID: 222665). 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) performed at Invitae indicates that this missense variant is not expected to disrupt KCND3 protein function with a negative predictive value of 80%. 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. |
Gene |
RCV001555788 | SCV001777255 | likely benign | not provided | 2021-06-17 | criteria provided, single submitter | clinical testing | Reported in a patient with features of cerebellar ataxia referred for whole exome sequencing; however, this variant was inherited from an unaffected mother (Coutelier et al., 2018); Reported in one ostensibly healthy control individual and in association with atrial fibrillation (Giudicessi et al., 2011; Mann et al., 2012); Published functional studies demonstrate no damaging effect (Mann et al., 2012); This variant is associated with the following publications: (PMID: 26220970, 23838598, 25175087, 25410959, 29482223, 22402074, 21349352) |
Institute of Human Genetics, |
RCV000558965 | SCV003803728 | uncertain significance | Spinocerebellar ataxia type 19/22 | criteria provided, single submitter | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV001555788 | SCV001927243 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV001555788 | SCV001973320 | likely benign | not provided | no assertion criteria provided | clinical testing | ||
Prevention |
RCV004737334 | SCV005357153 | uncertain significance | KCND3-related disorder | 2024-04-03 | no assertion criteria provided | clinical testing | The KCND3 c.641A>G variant is predicted to result in the amino acid substitution p.Lys214Arg. This variant has been reported in individuals with episodic gait disorder, Brugada syndrome, or atrial fibrillation (Coutelier et al 2018. PubMed ID: 29482223; Di Resta C et al 2015. PubMed ID: 26220970; Mann SA et al 2012. PubMed ID: 22402074). However, this variant was also inherited from an unaffected parent of a proband with episodic gait disorder and was identified in controls for the Brugada syndrome study (Coutelier et al 2018. PubMed ID: 29482223; Di Resta C et al 2015. PubMed ID: 26220970; Giudicessi JR et al 2011. PubMed ID: 21349352). An in vitro study of this variant showed no change in cellular electrophysiology (Mann SA et al 2012. PubMed ID: 22402074). This variant is reported in 0.034% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too frequent to be a primary cause of autosomal dominant disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |