VCV000188057.40 - ClinVar

NM_001244008.2(KIF1A):c.206C>T (p.Ser69Leu)

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.

(6)

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

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.206C>T (p.Ser69Leu)

Variation ID: 188057 Accession: VCV000188057.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 240788208 (GRCh38) [ NCBI UCSC ] 2: 241727625 (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 29, 2015	Oct 20, 2024	Dec 20, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001244008.2:c.206C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001230937.1:p.Ser69Leu	missense
NM_001320705.2:c.206C>T	NP_001307634.1:p.Ser69Leu	missense
NM_001330289.2:c.206C>T	NP_001317218.1:p.Ser69Leu	missense
NM_001330290.2:c.206C>T	NP_001317219.1:p.Ser69Leu	missense
NM_001379631.1:c.206C>T	NP_001366560.1:p.Ser69Leu	missense
NM_001379632.1:c.206C>T	NP_001366561.1:p.Ser69Leu	missense
NM_001379633.1:c.206C>T	NP_001366562.1:p.Ser69Leu	missense
NM_001379634.1:c.206C>T	NP_001366563.1:p.Ser69Leu	missense
NM_001379635.1:c.206C>T	NP_001366564.1:p.Ser69Leu	missense
NM_001379636.1:c.206C>T	NP_001366565.1:p.Ser69Leu	missense
NM_001379637.1:c.206C>T	NP_001366566.1:p.Ser69Leu	missense
NM_001379638.1:c.206C>T	NP_001366567.1:p.Ser69Leu	missense
NM_001379639.1:c.206C>T	NP_001366568.1:p.Ser69Leu	missense
NM_001379640.1:c.206C>T	NP_001366569.1:p.Ser69Leu	missense
NM_001379641.1:c.206C>T	NP_001366570.1:p.Ser69Leu	missense
NM_001379642.1:c.206C>T	NP_001366571.1:p.Ser69Leu	missense
NM_001379645.1:c.206C>T	NP_001366574.1:p.Ser69Leu	missense
NM_001379646.1:c.206C>T	NP_001366575.1:p.Ser69Leu	missense
NM_001379648.1:c.206C>T	NP_001366577.1:p.Ser69Leu	missense
NM_001379649.1:c.206C>T	NP_001366578.1:p.Ser69Leu	missense
NM_001379650.1:c.206C>T	NP_001366579.1:p.Ser69Leu	missense
NM_001379651.1:c.206C>T	NP_001366580.1:p.Ser69Leu	missense
NM_001379653.1:c.206C>T	NP_001366582.1:p.Ser69Leu	missense
NM_004321.8:c.206C>T	NP_004312.2:p.Ser69Leu	missense
NC_000002.12:g.240788208G>A
NC_000002.11:g.241727625G>A
NG_029724.1:g.37000C>T
LRG_367:g.37000C>T
LRG_367t1:c.206C>T	LRG_367p1:p.Ser69Leu
LRG_367t2:c.206C>T	LRG_367p2:p.Ser69Leu
	Q12756:p.Ser69Leu

... more HGVS ... less HGVS

Protein change

S69L

Other names

Canonical SPDI

NC_000002.12:240788207: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.

Links

ClinGen: CA346824 UniProtKB: Q12756#VAR_077467 OMIM: 601255.0014 dbSNP: rs786200949 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	2907	3116

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	Pathogenic (1)	no assertion criteria provided	Oct 27, 2014	RCV000167867.2
Hereditary spastic paraplegia 30 Intellectual disability, autosomal dominant 9 Neuropathy, hereditary sensory, type 2C	Pathogenic (1)	criteria provided, single submitter	Dec 20, 2022	RCV000693147.11
Hereditary spastic paraplegia 30	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 15, 2020	RCV001078152.5
not provided	Likely pathogenic (1)	criteria provided, single submitter	Apr 1, 2018	RCV000762334.23

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 (Dec 20, 2022)	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: SCV000821003.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 28492532‚ 25585697‚ 26410750 Comment: 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) … (more) 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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188057). This missense change has been observed in individual(s) with uncomplicated hereditary spastic paraplegia (PMID: 25585697, 26410750). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 69 of the KIF1A protein (p.Ser69Leu). (less)
Likely pathogenic (Apr 01, 2018)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000892642.28 First in ClinVar: Mar 31, 2019 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Likely pathogenic (Jun 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Hereditary spastic paraplegia 30 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV001426726.1 First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020	Publications: PubMed (5) PubMed: 25585697‚ 26410750‚ 29159194‚ 31488895‚ 32096284 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); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to moderate); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1 moderate); 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); (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 30 Affected status: yes Allele origin: unknown	Paris Brain Institute, Inserm - ICM Accession: SCV001451074.1 First in ClinVar: May 16, 2021 Last updated: May 16, 2021	Number of individuals with the variant: 3
Pathogenic (Oct 27, 2014)	no assertion criteria provided Method: research	Hereditary spastic paraplegia Affected status: yes Allele origin: inherited, de novo	Neuromuscular disorders lab, University of Helsinki Accession: SCV000191086.1 First in ClinVar: Mar 29, 2015 Last updated: Mar 29, 2015	Publications: PubMed (1) PubMed: 25585697 Observation 1: Observation 2:
Pathogenic (Jan 14, 2015)	no assertion criteria provided Method: literature only	SPASTIC PARAPLEGIA 30A, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV001244203.2 First in ClinVar: Apr 24, 2020 Last updated: Jul 15, 2024	Publications: PubMed (4) PubMed: 25585697‚ 26410750‚ 29159194‚ 31488895 Comment on evidence: In a father and son of Finnish descent with pure autosomal dominant spastic paraplegia-30A (SPG30A; 610357), Ylikallio et al. (2015) identified a heterozygous c.206C-T transition … (more) In a father and son of Finnish descent with pure autosomal dominant spastic paraplegia-30A (SPG30A; 610357), Ylikallio et al. (2015) identified a heterozygous c.206C-T transition (c.206C-T, NM_001244008.1) in the KIF1A gene, resulting in a ser69-to-leu (S69L) substitution at a moderately conserved residue in the motor domain. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was demonstrated to have occurred de novo in the father. The variant was not present in the 1000 Genomes Project or Exome Variant Server databases. Functional studies of the variant and studies of patient cells were not performed. In 4 affected members of a multigenerational Sicilian family with autosomal dominant SPG30A, Citterio et al. (2015) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. In 3 members of a 3-generation family with SPG30A, Roda et al. (2017) identified a heterozygous S69L mutation in the KIF1A gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed. Pennings et al. (2020) identified a heterozygous S69L mutation in 3 members of a multigenerational family (P3) with SPG30A. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant were not performed. (less)

Comment:

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. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 188057). This missense change has been observed in individual(s) with uncomplicated hereditary spastic paraplegia (PMID: 25585697, 26410750). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 69 of the KIF1A protein (p.Ser69Leu).

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); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to moderate); Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PP1 moderate); 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);

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
KIF1A-related disorders in children: A wide spectrum of central and peripheral nervous system involvement.	Nemani T	Journal of the peripheral nervous system : JPNS	2020	PMID: 32096284
KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.	Pennings M	European journal of human genetics : EJHG	2020	PMID: 31488895
Multigeneration family with dominant SPG30 hereditary spastic paraplegia.	Roda RH	Annals of clinical and translational neurology	2017	PMID: 29159194
Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis.	Citterio A	Journal of neurology	2015	PMID: 26410750
Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia.	Ylikallio E	European journal of human genetics : EJHG	2015	PMID: 25585697

Text-mined citations for rs786200949 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001244008.2(KIF1A):c.206C>T (p.Ser69Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs786200949 ...