VCV001802641.3 - ClinVar

NM_015656.2(KIF26A):c.4676C>T (p.Ala1559Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_015656.2(KIF26A):c.4676C>T (p.Ala1559Val)

Variation ID: 1802641 Accession: VCV001802641.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q32.33 14: 104177464 (GRCh38) [ NCBI UCSC ] 14: 104643801 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 11, 2022	Mar 30, 2024	Jan 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_015656.2:c.4676C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_056471.1:p.Ala1559Val	missense
NC_000014.9:g.104177464C>T
NC_000014.8:g.104643801C>T

Protein change

A1559V

Other names

Canonical SPDI

NC_000014.9:104177463:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 613231.0003 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
KIF26A		-	-	GRCh38 GRCh37	306	368

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cortical dysplasia, complex, with other brain malformations 11	Pathogenic (2)	criteria provided, single submitter	Nov 21, 2023	RCV002465480.2
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 22, 2024	RCV003988009.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cortical dysplasia, complex, with other brain malformations 11 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004183504.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Uncertain significance (Jan 22, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004803611.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (2) PubMed: 37486637‚ 36228617 Comment: Variant summary: KIF26A c.4676C>T (p.Ala1559Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: KIF26A c.4676C>T (p.Ala1559Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 1528980 control chromosomes, predominantly at a frequency of 0.0028 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. c.4676C>T has been reported in the literature in bi-allelic individuals affected with brain malformations and polymicrogyria (example: Qian_2022, Akula_2023). These reports do not provide unequivocal conclusions about association of the variant with Cortical Dysplasia, Complex, With Other Brain Malformations 11. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example: Qian_2022). The following publications have been ascertained in the context of this evaluation (PMID: 36228617, 37486637). ClinVar contains an entry for this variant (Variation ID: 1802641). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Pathogenic (Dec 08, 2022)	no assertion criteria provided Method: literature only	CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 11 Affected status: not provided Allele origin: germline	OMIM Accession: SCV002760178.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Publications: PubMed (1) PubMed: 36228617 Comment on evidence: For discussion of the c.4676C-T transition (c.4676C-T, NM_015656.1) in the KIF26A gene, resulting in an ala1559-to-val (A1559V) substitution, that was found in compound heterozygous state … (more) For discussion of the c.4676C-T transition (c.4676C-T, NM_015656.1) in the KIF26A gene, resulting in an ala1559-to-val (A1559V) substitution, that was found in compound heterozygous state in a fetus (family B) with complex cortical dysplasia with other brain malformations-11 (CDCBM11; 620156) by Qian et al. (2022), see 613231.0002. For discussion of the A1559V mutation in the KIF26A gene that was found in compound heterozygous state in 2 unrelated patients (families C and D) with CDCBM11 by Qian et al. (2022), see 613231.0004 and 613231.0005, respectively. (less)

Comment:

Variant summary: KIF26A c.4676C>T (p.Ala1559Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 1528980 control chromosomes, predominantly at a frequency of 0.0028 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. c.4676C>T has been reported in the literature in bi-allelic individuals affected with brain malformations and polymicrogyria (example: Qian_2022, Akula_2023). These reports do not provide unequivocal conclusions about association of the variant with Cortical Dysplasia, Complex, With Other Brain Malformations 11. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (example: Qian_2022). The following publications have been ascertained in the context of this evaluation (PMID: 36228617, 37486637). ClinVar contains an entry for this variant (Variation ID: 1802641). Based on the evidence outlined above, the variant was classified as uncertain significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria.	Akula SK	JAMA neurology	2023	PMID: 37486637
Loss of non-motor kinesin KIF26A causes congenital brain malformations via dysregulated neuronal migration and axonal growth as well as apoptosis.	Qian X	Developmental cell	2022	PMID: 36228617

Text-mined citations for this variant ...

Record last updated Mar 30, 2024

ClinVar Genomic variation as it relates to human health

NM_015656.2(KIF26A):c.4676C>T (p.Ala1559Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...