VCV000234725.53 - ClinVar

NM_001244008.2(KIF1A):c.3494T>C (p.Ile1165Thr)

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.

(15)

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
Uncertain significance(8); Benign(1); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001244008.2(KIF1A):c.3494T>C (p.Ile1165Thr)

Variation ID: 234725 Accession: VCV000234725.53

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 240744032 (GRCh38) [ NCBI UCSC ] 2: 241683449 (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 19, 2017	Nov 24, 2024	Feb 8, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001244008.2:c.3494T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001230937.1:p.Ile1165Thr	missense
NM_001320705.2:c.3218T>C	NP_001307634.1:p.Ile1073Thr	missense
NM_001330289.2:c.3218T>C	NP_001317218.1:p.Ile1073Thr	missense
NM_001330290.2:c.3293T>C	NP_001317219.1:p.Ile1098Thr	missense
NM_001379631.1:c.3569T>C	NP_001366560.1:p.Ile1190Thr	missense
NM_001379632.1:c.3443T>C	NP_001366561.1:p.Ile1148Thr	missense
NM_001379633.1:c.3467T>C	NP_001366562.1:p.Ile1156Thr	missense
NM_001379634.1:c.3293T>C	NP_001366563.1:p.Ile1098Thr	missense
NM_001379635.1:c.3293T>C	NP_001366564.1:p.Ile1098Thr	missense
NM_001379636.1:c.3191T>C	NP_001366565.1:p.Ile1064Thr	missense
NM_001379637.1:c.3266T>C	NP_001366566.1:p.Ile1089Thr	missense
NM_001379638.1:c.3218T>C	NP_001366567.1:p.Ile1073Thr	missense
NM_001379639.1:c.3191T>C	NP_001366568.1:p.Ile1064Thr	missense
NM_001379640.1:c.3188T>C	NP_001366569.1:p.Ile1063Thr	missense
NM_001379641.1:c.3191T>C	NP_001366570.1:p.Ile1064Thr	missense
NM_001379642.1:c.3467T>C	NP_001366571.1:p.Ile1156Thr	missense
NM_001379645.1:c.3467T>C	NP_001366574.1:p.Ile1156Thr	missense
NM_001379646.1:c.3293T>C	NP_001366575.1:p.Ile1098Thr	missense
NM_001379648.1:c.3266T>C	NP_001366577.1:p.Ile1089Thr	missense
NM_001379649.1:c.3191T>C	NP_001366578.1:p.Ile1064Thr	missense
NM_001379650.1:c.3191T>C	NP_001366579.1:p.Ile1064Thr	missense
NM_001379651.1:c.3191T>C	NP_001366580.1:p.Ile1064Thr	missense
NM_001379653.1:c.3191T>C	NP_001366582.1:p.Ile1064Thr	missense
NM_004321.7:c.3191T>C
NM_004321.8:c.3191T>C	NP_004312.2:p.Ile1064Thr	missense
NC_000002.12:g.240744032A>G
NC_000002.11:g.241683449A>G
NG_029724.1:g.81176T>C
LRG_367:g.81176T>C
LRG_367t1:c.3494T>C	LRG_367p1:p.Ile1165Thr
LRG_367t2:c.3191T>C

... more HGVS ... less HGVS

Protein change

I1064T, I1165T, I1073T, I1098T, I1063T, I1089T, I1148T, I1156T, I1190T

Other names

Canonical SPDI

NC_000002.12:240744031:A:G

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.

0.00040 (G)

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

The Genome Aggregation Database (gnomAD), exomes 0.00038

1000 Genomes Project 0.00040

Exome Aggregation Consortium (ExAC) 0.00046

1000 Genomes Project 30x 0.00062

The Genome Aggregation Database (gnomAD) 0.00063

Trans-Omics for Precision Medicine (TOPMed) 0.00071

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00103

Links

ClinGen: CA2207781 dbSNP: rs35698242 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.
not provided	Uncertain significance (9)	criteria provided, multiple submitters, no conflicts	Feb 8, 2024	RCV000213625.34
Hereditary spastic paraplegia	Uncertain significance (1)	criteria provided, single submitter	Oct 1, 2019	RCV001847946.3
History of neurodevelopmental disorder	Uncertain significance (1)	criteria provided, single submitter	May 12, 2020	RCV000718021.2
Hereditary spastic paraplegia 30 Intellectual disability, autosomal dominant 9 Neuropathy, hereditary sensory, type 2C	Likely benign (1)	criteria provided, single submitter	Jan 22, 2024	RCV000540329.14
Hereditary spastic paraplegia 30 Intellectual disability, autosomal dominant 9 Neuropathy, hereditary sensory and autonomic, type 2A Neuropathy, hereditary sensory, type 2C	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000764395.2
not specified	Benign (1)	criteria provided, single submitter	May 4, 2022	RCV002247667.1
Hereditary spastic paraplegia 30	Likely benign (1)	criteria provided, single submitter	Jul 17, 2023	RCV004786611.1

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 (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neuropathy, hereditary sensory and autonomic, type 2A Hereditary spastic paraplegia 30 Neuropathy, hereditary sensory, type 2C Intellectual disability, autosomal dominant 9 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895448.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely benign (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 30 Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398459.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 31455732‚ 31488895 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Dominant negative, loss of function and … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Variants with a dominant negative effect have been shown to cause NESCAV syndrome (MIM#614255; OMIM). Both loss and gain of function mechanisms have been reported for variants causing spastic paraplegia (MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMID: 31488895, 31455732). (I) 0108 - This gene is associated with both recessive and dominant disease. Genotype-phenotype correlation is not currently established. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. (I) 0200 - This variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2; 107 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a VUS and likely benign in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - Variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Uncertain significance (Nov 06, 2019)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001475201.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Uncertain significance (May 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001715795.2 First in ClinVar: Jun 15, 2021 Last updated: Jan 26, 2024	Number of individuals with the variant: 2
Uncertain significance (Oct 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002104860.1 First in ClinVar: Mar 19, 2022 Last updated: Mar 19, 2022
Benign (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517557.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Uncertain significance (Jan 12, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003814559.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Oct 01, 2022)	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: SCV004149666.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: KIF1A: PP2, BP4 Number of individuals with the variant: 1
Uncertain significance (Feb 08, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000279735.14 First in ClinVar: May 29, 2016 Last updated: Sep 29, 2024	Comment: Reported as a variant of uncertain significance in a patient with TattonBrownRahman syndrome who had a different genetic etiology explaining the phenotype (PMID: 38041495); In … (more) Reported as a variant of uncertain significance in a patient with TattonBrownRahman syndrome who had a different genetic etiology explaining the phenotype (PMID: 38041495); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 38041495) (less)
Likely benign (Jan 22, 2024)	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: SCV000638577.10 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532
Uncertain significance (May 12, 2020)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (2/2020)) Method: clinical testing	History of neurodevelopmental disorder Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000848882.3 First in ClinVar: Nov 08, 2018 Last updated: Dec 07, 2020	Comment: The p.I1064T variant (also known as c.3191T>C), located in coding exon 30 of the KIF1A gene, results from a T to C substitution at nucleotide … (more) The p.I1064T variant (also known as c.3191T>C), located in coding exon 30 of the KIF1A gene, results from a T to C substitution at nucleotide position 3191. The isoleucine at codon 1064 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less) Number of individuals with the variant: 1
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744309.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001918842.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001970129.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001749659.1 First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021	Comment: Variant interpreted as Likely benign and reported on 02-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Likely benign and reported on 02-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Hypermetropia (present) , Abnormality of the cardiovascular system (present) , Abnormal intestine morphology (present) , Abnormality of the pancreas (present) , Abnormal muscle physiology (present) … (more) Hypermetropia (present) , Abnormality of the cardiovascular system (present) , Abnormal intestine morphology (present) , Abnormality of the pancreas (present) , Abnormal muscle physiology (present) , Abnormality of the bladder (present) (less) Indication for testing: Diagnostic Age: 60-69 years Sex: male Testing laboratory: Invitae Date variant was reported to submitter: 2020-02-17 Testing laboratory interpretation: Likely benign
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Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Variants with a dominant negative effect have been shown to cause NESCAV syndrome (MIM#614255; OMIM). Both loss and gain of function mechanisms have been reported for variants causing spastic paraplegia (MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMID: 31488895, 31455732). (I) 0108 - This gene is associated with both recessive and dominant disease. Genotype-phenotype correlation is not currently established. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. (I) 0200 - This variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2; 107 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a VUS and likely benign in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - Variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Reported as a variant of uncertain significance in a patient with TattonBrownRahman syndrome who had a different genetic etiology explaining the phenotype (PMID: 38041495); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 38041495)

Comment:

The p.I1064T variant (also known as c.3191T>C), located in coding exon 30 of the KIF1A gene, results from a T to C substitution at nucleotide position 3191. The isoleucine at codon 1064 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

Variant interpreted as Likely benign and reported on 02-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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 variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.	Pennings M	European journal of human genetics : EJHG	2020	PMID: 31488895
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

Text-mined citations for rs35698242 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001244008.2(KIF1A):c.3494T>C (p.Ile1165Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs35698242 ...