ClinVar Miner

Submissions for variant NM_004522.3(KIF5C):c.709G>A (p.Glu237Lys) (rs587777570)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000128852 SCV000245500 pathogenic Cortical dysplasia, complex, with other brain malformations 2 2014-10-10 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice in our laboratory de novo: in an 18-year-old female with intellectual disability, seizure disorder, long face, microcephaly; in a 7-year-old male with global delays, seizures, retained baby teeth, autism, cortical dysplasia, aggression, poor balance, strabismus
GeneDx RCV000254976 SCV000321808 pathogenic not provided 2017-02-15 criteria provided, single submitter clinical testing E237K is a recurrent pathogenic variant that has been identified as a confirmed de novo variant in two unrelated individuals in the published literature with frontal pachygyria, severe developmental delay, and stereotypic movements, one of whom was also reported to have epilepsy and postnatal microcephaly (deLigt et al., 2012; Willemsen et al., 2014; Cavallin et al., 2016). Additionally, E237K has been identified as a confirmed de novo variant in other individuals undergoing testing at GeneDx and has been reported in ClinVar as a pathogenic variant by a different clinical laboratory (SVC0002455000.1; Landrum et al., 2015). Functional studies evaluating overexpression of E237K in rat hippocampal neurons indicate that this variant leads to a non-functional motor domain (Willemsen et al., 2014). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). It is a non-conservative amino acid substitution that occurs at a position that is well-conserved across species, and in silico analysis predicts this mutation is probably damaging to the protein structure/function. We interpret E237K as a pathogenic variant.
Institute of Human Genetics, Klinikum rechts der Isar RCV000128852 SCV000680273 pathogenic Cortical dysplasia, complex, with other brain malformations 2 2017-11-23 criteria provided, single submitter clinical testing
SIB Swiss Institute of Bioinformatics RCV000128852 SCV000803520 pathogenic Cortical dysplasia, complex, with other brain malformations 2 2018-05-31 criteria provided, single submitter curation This variant is interpreted as a Pathogenic, for Cortical dysplasia, complex, with other brain malformations 2, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM1 => Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation. located in the kinesin motor domain and microtubule-binding region (http://www.uniprot.org/uniprot/O60282#family_and_domains). PS3 => Well-established functional studies show a deleterious effect (PMID:24812067). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:29048727) (PMID:23033978). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => PS4 downgraded in strength to Moderate (PMID:23033978) (PMID:29048727).
Mendelics RCV000128852 SCV001135967 pathogenic Cortical dysplasia, complex, with other brain malformations 2 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000128852 SCV000172684 pathogenic Cortical dysplasia, complex, with other brain malformations 2 2014-07-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000128852 SCV001423307 not provided Cortical dysplasia, complex, with other brain malformations 2 no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 02-20-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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