This variant is interpreted as pathogenic for spastic paraplegia 30, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); De novo (paternity and maternity confirmed) (PS2); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to supporting); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1).
ClinVar Genomic variation as it relates to human health
NM_001244008.2(KIF1A):c.773C>T (p.Thr258Met)
Germline
Classification
Help
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.
(13)
Help
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.
Pathogenic/Likely pathogenic
13
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.773C>T (p.Thr258Met)
Variation ID: 464261 Accession: VCV000464261.52
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q37.3 2: 240783764 (GRCh38) [ NCBI UCSC ] 2: 241723181 (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 May 26, 2018 Oct 26, 2024 Jan 22, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001244008.2:c.773C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001230937.1:p.Thr258Met missense NM_001320705.2:c.773C>T NP_001307634.1:p.Thr258Met missense NM_001330289.2:c.773C>T NP_001317218.1:p.Thr258Met missense NM_001330290.2:c.773C>T NP_001317219.1:p.Thr258Met missense NM_001379631.1:c.773C>T NP_001366560.1:p.Thr258Met missense NM_001379632.1:c.773C>T NP_001366561.1:p.Thr258Met missense NM_001379633.1:c.773C>T NP_001366562.1:p.Thr258Met missense NM_001379634.1:c.773C>T NP_001366563.1:p.Thr258Met missense NM_001379635.1:c.773C>T NP_001366564.1:p.Thr258Met missense NM_001379636.1:c.773C>T NP_001366565.1:p.Thr258Met missense NM_001379637.1:c.773C>T NP_001366566.1:p.Thr258Met missense NM_001379638.1:c.773C>T NP_001366567.1:p.Thr258Met missense NM_001379639.1:c.773C>T NP_001366568.1:p.Thr258Met missense NM_001379640.1:c.773C>T NP_001366569.1:p.Thr258Met missense NM_001379641.1:c.773C>T NP_001366570.1:p.Thr258Met missense NM_001379642.1:c.773C>T NP_001366571.1:p.Thr258Met missense NM_001379645.1:c.773C>T NP_001366574.1:p.Thr258Met missense NM_001379646.1:c.773C>T NP_001366575.1:p.Thr258Met missense NM_001379648.1:c.773C>T NP_001366577.1:p.Thr258Met missense NM_001379649.1:c.773C>T NP_001366578.1:p.Thr258Met missense NM_001379650.1:c.773C>T NP_001366579.1:p.Thr258Met missense NM_001379651.1:c.773C>T NP_001366580.1:p.Thr258Met missense NM_001379653.1:c.773C>T NP_001366582.1:p.Thr258Met missense NM_004321.8:c.773C>T NP_004312.2:p.Thr258Met missense NC_000002.12:g.240783764G>A NC_000002.11:g.241723181G>A NG_029724.1:g.41444C>T LRG_367:g.41444C>T LRG_367t1:c.773C>T LRG_367p1:p.Thr258Met LRG_367t2:c.773C>T LRG_367p2:p.Thr258Met - Protein change
- T258M
- Other names
- -
- Canonical SPDI
- NC_000002.12:240783763:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 22, 2024 | RCV000548642.17 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Apr 27, 2023 | RCV001251233.13 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Apr 9, 2018 | RCV001266365.9 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 13, 2023 | RCV001268098.12 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2021 | RCV001770432.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 2, 2021 | RCV001848939.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 11, 2021 | RCV002289760.9 |
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
(Jun 15, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary spastic paraplegia 30
Affected status: unknown
Allele origin:
unknown
|
SIB Swiss Institute of Bioinformatics
Accession: SCV001426732.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
Comment:
This variant is interpreted as pathogenic for spastic paraplegia 30, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low … (more)
This variant is interpreted as pathogenic for spastic paraplegia 30, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); De novo (paternity and maternity confirmed) (PS2); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to supporting); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1). (less)
|
|
|
Likely pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal unknown)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446752.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Spastic paraplegia (present) , Spastic gait (present) , Gait ataxia (present) , Somatic sensory dysfunction (present) , Progressive spastic paraplegia (present)
Sex: female
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 30
Affected status: yes
Allele origin:
unknown
|
Paris Brain Institute, Inserm - ICM
Accession: SCV001451088.1
First in ClinVar: May 16, 2021 Last updated: May 16, 2021 |
Number of individuals with the variant: 4
|
|
|
Pathogenic
(Jun 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001789235.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Published functional studies demonstrate a damaging effect (Cheon et al., 2017; Guedes-Dias et al., 2019); In silico analysis supports that this missense variant has a … (more)
Published functional studies demonstrate a damaging effect (Cheon et al., 2017; Guedes-Dias et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33880452, 27535533, 32045731, 32935419, 30612907, 31488895, 28970574) (less)
|
|
|
Pathogenic
(Nov 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV002105271.1
First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022 |
|
|
|
Pathogenic
(Oct 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Neuropathy, hereditary sensory, type 2C
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580424.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM6_STR, PS4_MOD, PM2_SUP, PP1, PP2, PP3
|
Number of individuals with the variant: 1
Sex: female
|
|
|
Likely pathogenic
(Apr 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001444539.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Autistic disorder of childhood onset (present) , Neurodevelopmental delay (present) , Peripheral neuropathy (present) , Anxiety (present) , Diarrhea (present) , Muscular hypotonia (present) , … (more)
Autistic disorder of childhood onset (present) , Neurodevelopmental delay (present) , Peripheral neuropathy (present) , Anxiety (present) , Diarrhea (present) , Muscular hypotonia (present) , Gait disturbance (present) , Macrocephalus (present) , Short stature (present) , Obsessive-compulsive behavior (present) , Skin ulcer (present) (less)
Sex: male
Ethnicity/Population group: Ashkenazi Jewish
|
|
|
Likely pathogenic
(Apr 27, 2023)
|
criteria provided, single submitter
Method: research
|
Hereditary spastic paraplegia 30
Affected status: yes
Allele origin:
germline
|
Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)
Accession: SCV003920772.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
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: SCV000638638.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 258 of the KIF1A protein (p.Thr258Met). … (more)
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 258 of the KIF1A protein (p.Thr258Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of HSP and hereditary spastic paraplegia (HSP) (PMID: 28970574; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 464261). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KIF1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KIF1A function (PMID: 28970574). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198583.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Hereditary spastic paraplegia 30
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760077.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
|
Pathogenic
(Sep 16, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Intellectual disability, autosomal dominant 9
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein
Accession: SCV002011705.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
|
|
|
Likely pathogenic
(Jun 01, 2022)
|
no assertion criteria provided
Method: provider interpretation
|
Hereditary spastic paraplegia 30
Affected status: yes
Allele origin:
inherited
|
Solve-RD Consortium
Accession: SCV005091536.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
Comment:
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and … (more)
Variant identified during reanalysis of unsolved cases by the Solve-RD project. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. (less)
|
Comment:
Variant confirmed as disease-causing by referring clinical team
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Published functional studies demonstrate a damaging effect (Cheon et al., 2017; Guedes-Dias et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33880452, 27535533, 32045731, 32935419, 30612907, 31488895, 28970574)
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 258 of the KIF1A protein (p.Thr258Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of HSP and hereditary spastic paraplegia (HSP) (PMID: 28970574; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 464261). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KIF1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KIF1A function (PMID: 28970574). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant confirmed as disease-causing by referring clinical team
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:
This variant is interpreted as pathogenic for spastic paraplegia 30, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); De novo (paternity and maternity confirmed) (PS2); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to supporting); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1).
Comment:
Published functional studies demonstrate a damaging effect (Cheon et al., 2017; Guedes-Dias et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33880452, 27535533, 32045731, 32935419, 30612907, 31488895, 28970574)
Comment:
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 258 of the KIF1A protein (p.Thr258Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of HSP and hereditary spastic paraplegia (HSP) (PMID: 28970574; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 464261). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KIF1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KIF1A function (PMID: 28970574). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant confirmed as disease-causing by referring clinical team
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia. | Pennings M | European journal of human genetics : EJHG | 2020 | PMID: 31488895 |
| 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 |
| Novel De Novo Mutations in KIF1A as a Cause of Hereditary Spastic Paraplegia With Progressive Central Nervous System Involvement. | Hotchkiss L | Journal of child neurology | 2016 | PMID: 27034427 |
Text-mined citations for rs1553638086 ...
HelpThese 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 Oct 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.