VCV001428612.5 - ClinVar

NM_001244008.2(KIF1A):c.2977+4C>T

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001244008.2(KIF1A):c.2977+4C>T

Variation ID: 1428612 Accession: VCV001428612.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 240750425 (GRCh38) [ NCBI UCSC ] 2: 241689842 (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	Mar 28, 2022	Nov 24, 2024	Dec 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001244008.2:c.2977+4C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001320705.2:c.2701+4C>T		intron variant
NM_001330289.2:c.2701+4C>T		intron variant
NM_001330290.2:c.2776+4C>T		intron variant
NM_001379631.1:c.3052+4C>T		intron variant
NM_001379632.1:c.2926+4C>T		intron variant
NM_001379633.1:c.2950+4C>T		intron variant
NM_001379634.1:c.2776+4C>T		intron variant
NM_001379635.1:c.2776+4C>T		intron variant
NM_001379636.1:c.2674+4C>T		intron variant
NM_001379637.1:c.2749+4C>T		intron variant
NM_001379638.1:c.2701+4C>T		intron variant
NM_001379639.1:c.2674+4C>T		intron variant
NM_001379640.1:c.2674+4C>T		intron variant
NM_001379641.1:c.2674+4C>T		intron variant
NM_001379642.1:c.2950+4C>T		intron variant
NM_001379645.1:c.2950+4C>T		intron variant
NM_001379646.1:c.2776+4C>T		intron variant
NM_001379648.1:c.2749+4C>T		intron variant
NM_001379649.1:c.2674+4C>T		intron variant
NM_001379650.1:c.2674+4C>T		intron variant
NM_001379651.1:c.2674+4C>T		intron variant
NM_001379653.1:c.2674+4C>T		intron variant
NM_004321.7:c.2674+4C>T
NM_004321.8:c.2674+4C>T		intron variant
NC_000002.12:g.240750425G>A
NC_000002.11:g.241689842G>A
NG_029724.1:g.74783C>T
LRG_367:g.74783C>T
LRG_367t2:c.2674+4C>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:240750424:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

dbSNP: rs1447106610 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.
KIF1A		No evidence available	No evidence available	GRCh38 GRCh37	2906	3115

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.
Hereditary spastic paraplegia 30 Intellectual disability, autosomal dominant 9 Neuropathy, hereditary sensory, type 2C	Uncertain significance (1)	criteria provided, single submitter	Dec 2, 2023	RCV001964923.4
KIF1A related neurological disorder	Uncertain significance (1)	criteria provided, single submitter	May 21, 2020	RCV004785396.1

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.
Uncertain significance (Dec 02, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary spastic paraplegia 30 Neuropathy, hereditary sensory, type 2C Intellectual disability, autosomal dominant 9 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002197663.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 17576681‚ 9536098 Comment: This sequence change falls in intron 25 of the KIF1A gene. It does not directly change the encoded amino acid sequence of the KIF1A protein. … (more) This sequence change falls in intron 25 of the KIF1A gene. It does not directly change the encoded amino acid sequence of the KIF1A protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1428612). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. (less)
Uncertain significance (May 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KIF1A related neurological disorder Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398105.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (3) PubMed: 22258533‚ 28970574‚ 31455732 Comment: Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms … (more) Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (Klebe, S. et al. (2012), Chiba, K. et al. (2019)). (N) 0104 - Dominant Negative is a mechanism of disease for this gene (Cheon, C. et al. (2017)). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0212 - Non-canonical splice variant without proven consequence on splicing (no functional evidence available) (intron 26). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (B) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)

Comment:

This sequence change falls in intron 25 of the KIF1A gene. It does not directly change the encoded amino acid sequence of the KIF1A protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1428612). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene (Klebe, S. et al. (2012), Chiba, K. et al. (2019)). (N) 0104 - Dominant Negative is a mechanism of disease for this gene (Cheon, C. et al. (2017)). (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0212 - Non-canonical splice variant without proven consequence on splicing (no functional evidence available) (intron 26). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. (B) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0807 - Variant has not previously been reported in a clinical context. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

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
Disease-associated mutations hyperactivate KIF1A motility and anterograde axonal transport of synaptic vesicle precursors.	Chiba K	Proceedings of the National Academy of Sciences of the United States of America	2019	PMID: 31455732
Autosomal dominant transmission of complicated hereditary spastic paraplegia due to a dominant negative mutation of KIF1A, SPG30 gene.	Cheon CK	Scientific reports	2017	PMID: 28970574
KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations.	Klebe S	European journal of human genetics : EJHG	2012	PMID: 22258533
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs1447106610 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001244008.2(KIF1A):c.2977+4C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1447106610 ...