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

dbSNP: rs587777570

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000128852	SCV000245500	pathogenic	Complex cortical dysplasia 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	2024-07-02	criteria provided, single submitter	clinical testing	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)
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000128852	SCV000680273	pathogenic	Complex cortical dysplasia with other brain malformations 2	2017-11-23	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000128852	SCV000803520	pathogenic	Complex cortical dysplasia 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	Complex cortical dysplasia with other brain malformations 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000254976	SCV002563591	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	KIF5C: PM2, PM5, PM6, PP2, PP3, PS3:Supporting, PS4:Supporting
Lifecell International Pvt. Ltd	RCV000128852	SCV003924375	pathogenic	Complex cortical dysplasia with other brain malformations 2		criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000128852	SCV004020981	pathogenic	Complex cortical dysplasia with other brain malformations 2	2023-06-23	criteria provided, single submitter	clinical testing	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.
Institute of Human Genetics, Heidelberg University	RCV000128852	SCV004814179	likely pathogenic	Complex cortical dysplasia with other brain malformations 2	2023-10-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000254976	SCV005196713	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000128852	SCV005368375	pathogenic	Complex cortical dysplasia with other brain malformations 2	2024-09-05	criteria provided, single submitter	clinical testing	Criteria applied: PS2,PS4,PM2,PM5,PP3,PP2
OMIM	RCV000128852	SCV000172684	pathogenic	Complex cortical dysplasia with other brain malformations 2	2014-07-01	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000128852	SCV001423307	not provided	Complex cortical dysplasia 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.