VCV000208161.39 - ClinVar

NM_001244008.2(KIF1A):c.647G>A (p.Arg216His)

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.

(9)

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.647G>A (p.Arg216His)

Variation ID: 208161 Accession: VCV000208161.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 240785062 (GRCh38) [ NCBI UCSC ] 2: 241724479 (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	Feb 9, 2016	Nov 24, 2024	Sep 21, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001244008.2:c.647G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001230937.1:p.Arg216His	missense
NM_001320705.2:c.647G>A	NP_001307634.1:p.Arg216His	missense
NM_001330289.2:c.647G>A	NP_001317218.1:p.Arg216His	missense
NM_001330290.2:c.647G>A	NP_001317219.1:p.Arg216His	missense
NM_001379631.1:c.647G>A	NP_001366560.1:p.Arg216His	missense
NM_001379632.1:c.647G>A	NP_001366561.1:p.Arg216His	missense
NM_001379633.1:c.647G>A	NP_001366562.1:p.Arg216His	missense
NM_001379634.1:c.647G>A	NP_001366563.1:p.Arg216His	missense
NM_001379635.1:c.647G>A	NP_001366564.1:p.Arg216His	missense
NM_001379636.1:c.647G>A	NP_001366565.1:p.Arg216His	missense
NM_001379637.1:c.647G>A	NP_001366566.1:p.Arg216His	missense
NM_001379638.1:c.647G>A	NP_001366567.1:p.Arg216His	missense
NM_001379639.1:c.647G>A	NP_001366568.1:p.Arg216His	missense
NM_001379640.1:c.647G>A	NP_001366569.1:p.Arg216His	missense
NM_001379641.1:c.647G>A	NP_001366570.1:p.Arg216His	missense
NM_001379642.1:c.647G>A	NP_001366571.1:p.Arg216His	missense
NM_001379645.1:c.647G>A	NP_001366574.1:p.Arg216His	missense
NM_001379646.1:c.647G>A	NP_001366575.1:p.Arg216His	missense
NM_001379648.1:c.647G>A	NP_001366577.1:p.Arg216His	missense
NM_001379649.1:c.647G>A	NP_001366578.1:p.Arg216His	missense
NM_001379650.1:c.647G>A	NP_001366579.1:p.Arg216His	missense
NM_001379651.1:c.647G>A	NP_001366580.1:p.Arg216His	missense
NM_001379653.1:c.647G>A	NP_001366582.1:p.Arg216His	missense
NM_004321.6:c.647G>A
NM_004321.8:c.647G>A	NP_004312.2:p.Arg216His	missense
NC_000002.12:g.240785062C>T
NC_000002.11:g.241724479C>T
NG_029724.1:g.40146G>A
LRG_367:g.40146G>A
LRG_367t1:c.647G>A	LRG_367p1:p.Arg216His
LRG_367t2:c.647G>A	LRG_367p2:p.Arg216His
	Q12756:p.Arg216His

... more HGVS ... less HGVS

Protein change

R216H

Other names

Canonical SPDI

NC_000002.12:240785061:C:T

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

OMIM: 601255.0010 dbSNP: rs672601368 ClinGen: CA204977 UniProtKB: Q12756#VAR_075482 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.
PEHO syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 7, 2015	RCV000207040.2
Intellectual disability, autosomal dominant 9	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 21, 2024	RCV000191021.8
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	May 16, 2022	RCV000997715.30
KIF1A-related disorder	not provided (1)	no classification provided	-	RCV003223396.3

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 (Aug 07, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: literature only	PEHO syndrome Affected status: yes Allele origin: de novo	Child and Family Research Institute Accession: SCV000243780.1 First in ClinVar: Feb 09, 2016 Last updated: Feb 09, 2016	Publications: PubMed (2) PubMed: 26486474‚ 26125038 Number of individuals with the variant: 1 Clinical Features: severe motor delay (present) , optic neuropathy (present) , hypotonia (present) , hyperreflexia (present) , spastic paraparesis (present) , seizures (present) , progressive disease (present) … (more) severe motor delay (present) , optic neuropathy (present) , hypotonia (present) , hyperreflexia (present) , spastic paraparesis (present) , seizures (present) , progressive disease (present) , cerebellar atrophy (present) , thinning of the corpus callosum (present) , postnatal cataracts (present) , peripheral neuropathy (present) (less) Sex: male Tissue: blood
Likely pathogenic (Jun 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Intellectual disability, autosomal dominant 9 Affected status: unknown Allele origin: unknown	SIB Swiss Institute of Bioinformatics Accession: SCV001426714.1 First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020	Publications: PubMed (1) PubMed: 26125038 Comment: This variant is interpreted as likely pathogenic for NESCAV syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low … (more) This variant is interpreted as likely pathogenic for NESCAV syndrome, 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); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); 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); Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5). (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447218.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Global developmental delay (present) , Brain atrophy (present) , Short stature (present) Sex: female
Likely pathogenic (Sep 10, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002016805.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Jun 01, 2017)	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: SCV001153390.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (May 16, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002520214.2 First in ClinVar: May 28, 2022 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); 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: 28332297, 26486474, 29691679, 26125038, 30862385, 31785789, 33880452, 21820098, 21376300) (less)
Pathogenic (Sep 21, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Intellectual disability, autosomal dominant 9 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398955.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (6) PubMed: 25265257‚ 26125038‚ 27848944‚ 31455732‚ 31488895‚ 32737135 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative effect has 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, MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMID: 31488895, 31455732). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Genotype-phenotype correlation is currently unestablished. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. Only the correlation for HSAN2 (MIM#614213) is established with all patients except for one, carrying null variants outside the motor domain (PMID: 32737135). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in the kinesin motor domain which is a hotspot in KIF1A (DECIPHER, OMIM). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative amino acid changes, p.(Arg216Pro) and p.(Arg216Cys) have been reported as pathogenic in more than ten individuals, including two heterozygous de novo patients with KIF1A-related features (ClinVar, PMIDs: 25265257, 26125038). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported at least six times as likely pathogenic/pathogenic, with three reports of de novo inheritance in heterozygous individuals with KIF1A-related features (ClinVar, PMIDs: 27848944, 26125038). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Jun 01, 2015)	no assertion criteria provided Method: literature only	NESCAV SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000245999.4 First in ClinVar: Sep 29, 2015 Last updated: Apr 15, 2020	Publications: PubMed (1) PubMed: 26125038 Comment on evidence: In a 16-year-old boy (patient 5) with NESCAV syndrome (NESCAVS; 614255), Esmaeeli Nieh et al. (2015) identified a de novo heterozygous c.647G-A transition (c.647G-A, NM_001244008) … (more) In a 16-year-old boy (patient 5) with NESCAV syndrome (NESCAVS; 614255), Esmaeeli Nieh et al. (2015) identified a de novo heterozygous c.647G-A transition (c.647G-A, NM_001244008) in the KIF1A gene, resulting in an arg216-to-his (R216H) substitution at a highly conserved residue in the motor domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project (ESP6500) databases. Functional studies of this variant were not performed, but an in vitro microtubule gliding assay of a mutation at the same residue (R216C; 601255.0009) showed that the R216C mutant protein had no motility. This patient also carried a missense variant of unknown significance in the NID1 gene (T408K; 131390), which may have explained his cataracts. (less)
not provided (-)	no classification provided Method: phenotyping only	KIF1A-related disorder Affected status: yes Allele origin: de novo	GenomeConnect - Brain Gene Registry Accession: SCV003918870.1 First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023	Comment: Variant interpreted as Pathogenic and reported on 09-21-2022 by lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect … (more) Variant interpreted as Pathogenic and reported on 09-21-2022 by lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. (less) Clinical Features: Abnormality of eye movement (present) , Generalized hypotonia (present) , Abnormal muscle physiology (present) Indication for testing: Diagnostic Zygosity: Single Heterozygote Age: 0-9 years Sex: female Method: Exome Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2022-09-21 Testing laboratory interpretation: Pathogenic

Comment:

This variant is interpreted as likely pathogenic for NESCAV syndrome, 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); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); 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); Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5).

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); 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: 28332297, 26486474, 29691679, 26125038, 30862385, 31785789, 33880452, 21820098, 21376300)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative effect has 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, MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMID: 31488895, 31455732). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Genotype-phenotype correlation is currently unestablished. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. Only the correlation for HSAN2 (MIM#614213) is established with all patients except for one, carrying null variants outside the motor domain (PMID: 32737135). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located in the kinesin motor domain which is a hotspot in KIF1A (DECIPHER, OMIM). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Two alternative amino acid changes, p.(Arg216Pro) and p.(Arg216Cys) have been reported as pathogenic in more than ten individuals, including two heterozygous de novo patients with KIF1A-related features (ClinVar, PMIDs: 25265257, 26125038). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported at least six times as likely pathogenic/pathogenic, with three reports of de novo inheritance in heterozygous individuals with KIF1A-related features (ClinVar, PMIDs: 27848944, 26125038). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

Variant interpreted as Pathogenic and reported on 09-21-2022 by lab GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect.

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
Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.	Nicita F	Journal of medical genetics	2021	PMID: 32737135
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
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.	Trujillano D	European journal of human genetics : EJHG	2017	PMID: 27848944
De novo dominant variants affecting the motor domain of KIF1A are a cause of PEHO syndrome.	Langlois S	European journal of human genetics : EJHG	2016	PMID: 26486474
De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy.	Esmaeeli Nieh S	Annals of clinical and translational neurology	2015	PMID: 26125038
De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.	Lee JR	Human mutation	2015	PMID: 25265257

Text-mined citations for rs672601368 ...

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.647G>A (p.Arg216His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs672601368 ...