This variant is interpreted as likely 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); Assumed de novo, but no confirmation of paternity and maternity (PM6); 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); Located in a mutational hot spot and/or critical and well-established functional domain (located in the ATP binding region) without benign variation (PM1).
ClinVar Genomic variation as it relates to human health
NM_001244008.2(KIF1A):c.304G>A (p.Gly102Ser)
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.
(6)
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
6
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.304G>A (p.Gly102Ser)
Variation ID: 422067 Accession: VCV000422067.14
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q37.3 2: 240788110 (GRCh38) [ NCBI UCSC ] 2: 241727527 (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 Apr 27, 2017 Feb 28, 2024 Feb 24, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001244008.2:c.304G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001230937.1:p.Gly102Ser missense NM_001244008.1:c.304G>A NM_001320705.2:c.304G>A NP_001307634.1:p.Gly102Ser missense NM_001330289.2:c.304G>A NP_001317218.1:p.Gly102Ser missense NM_001330290.2:c.304G>A NP_001317219.1:p.Gly102Ser missense NM_001379631.1:c.304G>A NP_001366560.1:p.Gly102Ser missense NM_001379632.1:c.304G>A NP_001366561.1:p.Gly102Ser missense NM_001379633.1:c.304G>A NP_001366562.1:p.Gly102Ser missense NM_001379634.1:c.304G>A NP_001366563.1:p.Gly102Ser missense NM_001379635.1:c.304G>A NP_001366564.1:p.Gly102Ser missense NM_001379636.1:c.304G>A NP_001366565.1:p.Gly102Ser missense NM_001379637.1:c.304G>A NP_001366566.1:p.Gly102Ser missense NM_001379638.1:c.304G>A NP_001366567.1:p.Gly102Ser missense NM_001379639.1:c.304G>A NP_001366568.1:p.Gly102Ser missense NM_001379640.1:c.304G>A NP_001366569.1:p.Gly102Ser missense NM_001379641.1:c.304G>A NP_001366570.1:p.Gly102Ser missense NM_001379642.1:c.304G>A NP_001366571.1:p.Gly102Ser missense NM_001379645.1:c.304G>A NP_001366574.1:p.Gly102Ser missense NM_001379646.1:c.304G>A NP_001366575.1:p.Gly102Ser missense NM_001379648.1:c.304G>A NP_001366577.1:p.Gly102Ser missense NM_001379649.1:c.304G>A NP_001366578.1:p.Gly102Ser missense NM_001379650.1:c.304G>A NP_001366579.1:p.Gly102Ser missense NM_001379651.1:c.304G>A NP_001366580.1:p.Gly102Ser missense NM_001379653.1:c.304G>A NP_001366582.1:p.Gly102Ser missense NM_004321.8:c.304G>A NP_004312.2:p.Gly102Ser missense NC_000002.12:g.240788110C>T NC_000002.11:g.241727527C>T NG_029724.1:g.37098G>A LRG_367:g.37098G>A LRG_367t2:c.304G>A LRG_367p2:p.Gly102Ser - Protein change
- G102S
- Other names
- -
- Canonical SPDI
- NC_000002.12:240788109:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
Unknown function
-
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 (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 6, 2022 | RCV000487011.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 13, 2021 | RCV000534578.6 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 24, 2023 | RCV001251229.4 |
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. |
|
|---|---|---|---|---|---|
|
Likely 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: SCV001426727.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
Comment:
This variant is interpreted as likely pathogenic for spastic paraplegia 30, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely … (more)
This variant is interpreted as likely 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); Assumed de novo, but no confirmation of paternity and maternity (PM6); 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); Located in a mutational hot spot and/or critical and well-established functional domain (located in the ATP binding region) without benign variation (PM1). (less)
|
|
|
Pathogenic
(Aug 24, 2020)
|
criteria provided, single submitter
Method: research
|
Hereditary spastic paraplegia 30
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV001430918.1
First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020 |
Comment:
This variant was identified as de novo in an individual with spastic paraplegia.
Sex: male
|
|
|
Pathogenic
(Jan 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000571446.7
First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate the variant results in loss of … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate the variant results in loss of protein expression along neurite lengths (Boyle et al., 2021); This variant is associated with the following publications: (PMID: 28332297, 26410750, 29934652, 31488895, 26125038, 21820098, 21376300, 28970574, 33880452, 34121983, 32935419, 31805580) (less)
|
|
|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002010617.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Pathogenic
(Oct 13, 2021)
|
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: SCV000651705.5
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with hereditary spastic paraparesis and/or spastic diplegia (PMID: 26410750; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 102 of the KIF1A protein (p.Gly102Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. (less)
|
|
|
Pathogenic
(Feb 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary spastic paraplegia 30
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003845169.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: KIF1A c.304G>A (p.Gly102Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: KIF1A c.304G>A (p.Gly102Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 235410 control chromosomes. c.304G>A has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia 30 or related disorders (de novo or familial cases). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that p.G102S leads to decrease of neurite tip accumulation (Boyle_2021). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. In addition, G102D has been reported to associate with disease. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
Comment:
Comment:
This variant was identified as de novo in an individual with spastic paraplegia.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate the variant results in loss of protein expression along neurite lengths (Boyle et al., 2021); This variant is associated with the following publications: (PMID: 28332297, 26410750, 29934652, 31488895, 26125038, 21820098, 21376300, 28970574, 33880452, 34121983, 32935419, 31805580)
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with hereditary spastic paraparesis and/or spastic diplegia (PMID: 26410750; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 102 of the KIF1A protein (p.Gly102Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine.
Comment:
Variant summary: KIF1A c.304G>A (p.Gly102Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 235410 control chromosomes. c.304G>A has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia 30 or related disorders (de novo or familial cases). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that p.G102S leads to decrease of neurite tip accumulation (Boyle_2021). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. In addition, G102D has been reported to associate with disease. Based on the evidence outlined above, the variant was classified as pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Unknown function
|
|
|
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Accession: SCV001430918.1
|
|
Comment:
This variant is interpreted as likely 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); Assumed de novo, but no confirmation of paternity and maternity (PM6); 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); Located in a mutational hot spot and/or critical and well-established functional domain (located in the ATP binding region) without benign variation (PM1).
Comment:
This variant was identified as de novo in an individual with spastic paraplegia.
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate the variant results in loss of protein expression along neurite lengths (Boyle et al., 2021); This variant is associated with the following publications: (PMID: 28332297, 26410750, 29934652, 31488895, 26125038, 21820098, 21376300, 28970574, 33880452, 34121983, 32935419, 31805580)
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with hereditary spastic paraparesis and/or spastic diplegia (PMID: 26410750; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 102 of the KIF1A protein (p.Gly102Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine.
Comment:
Variant summary: KIF1A c.304G>A (p.Gly102Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 235410 control chromosomes. c.304G>A has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia 30 or related disorders (de novo or familial cases). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that p.G102S leads to decrease of neurite tip accumulation (Boyle_2021). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. In addition, G102D has been reported to associate with disease. Based on the evidence outlined above, the variant was classified as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A-associated neurological disorder. | Boyle L | HGG advances | 2021 | PMID: 33880452 |
| Targeted next-generation sequencing improves diagnosis of hereditary spastic paraplegia in Chinese patients. | Lu C | Journal of molecular medicine (Berlin, Germany) | 2018 | PMID: 29934652 |
| Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis. | Citterio A | Journal of neurology | 2015 | PMID: 26410750 |
Text-mined citations for rs1064795534 ...
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 Sep 29, 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.