ClinVar Genomic variation as it relates to human health

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

Published functional studies demonstrate a damaging effect (PMID: 24812067); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23033978, 28191890, 29671837, 34490615, 26384676, 28867141, 28135719, 29048727, 26633545, 31101064, 31618753, 32562872, 31785789, 37486637, 33057194, 36122673, 35982159, 35231114, 24812067)

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).

A Heterozygous Missense variant c.709G>A in Exon 8 of the KIF5C gene that results in the amino acid substitution p.Glu237Lys was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID:140740]. The observed variation has previosuly been reported for complex cortical dysplasia with other brain malformations-2. Well-established functional studies show a deleterious effect by Willemsen, Marjolein H., et al., 2014. For these reasons this variant has been classified as Pathogenic.

Variant summary: KIF5C c.709G>A (p.Glu237Lys) results in a conservative amino acid change located in the Kinesin motor domain (IPR001752) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 243890 control chromosomes (gnomAD). c.709G>A has been reported in the literature in individuals affected with Complex Cortical Dysplasia, microcephaly, developmental disorders, and seizures, including several de novo occurrences (e.g., deLigt_2012, Michels_2017, vanderVen_2021, Duan_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35231114, 29048727, 23033978, 34490615). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Additionally, another missense variant affecting the same codon, c.710A>T (p.E237V), has been identified in four siblings affected with severe malformations of cortical development and microcephaly, and experimental studies found the variant results in complete absence of detectable ATP hydrolysis and protein mislocalization (PMID: 23603762). Based on the evidence outlined above, the variant was classified as pathogenic.

Criteria applied: PS2,PS4,PM2,PM5,PP3,PP2

KIF5C: PM2, PM5, PM6, PP2, PP3, PS3:Supporting, PS4:Supporting

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.