VCV001032652.8 - ClinVar

NM_001365951.3(KIF1B):c.3434G>A (p.Arg1145His)

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.

(4)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001365951.3(KIF1B):c.3434G>A (p.Arg1145His)

Variation ID: 1032652 Accession: VCV001032652.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.22 1: 10339780 (GRCh38) [ NCBI UCSC ] 1: 10399838 (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 22, 2021	May 1, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001365951.3:c.3434G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001352880.1:p.Arg1145His	missense
NM_001365952.1:c.3434G>A	NP_001352881.1:p.Arg1145His	missense
NM_015074.3:c.3296G>A	NP_055889.2:p.Arg1099His	missense
NC_000001.11:g.10339780G>A
NC_000001.10:g.10399838G>A
NG_008069.1:g.134075G>A
LRG_252:g.134075G>A
LRG_252t1:c.3296G>A	LRG_252p1:p.Arg1099His
LRG_252t2:c.3434G>A	LRG_252p2:p.Arg1145His

... more HGVS ... less HGVS

Protein change

R1145H, R1099H

Other names

Canonical SPDI

NC_000001.11:10339779: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

dbSNP: rs373663596 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.
KIF1B		-	-	GRCh38 GRCh37	2823	3113

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.
Pheochromocytoma	Uncertain significance (1)	criteria provided, single submitter	Oct 16, 2018	RCV001334807.1
Charcot-Marie-Tooth disease type 2	Uncertain significance (1)	criteria provided, single submitter	Jan 31, 2024	RCV001341321.5
Charcot-Marie-Tooth disease type 2A1 Neuroblastoma, susceptibility to, 1 Pheochromocytoma	Uncertain significance (1)	criteria provided, single submitter	Dec 23, 2021	RCV002504522.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Dec 25, 2022	RCV004035783.1

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 16, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pheochromocytoma Affected status: yes Allele origin: paternal	Baylor Genetics Accession: SCV001527770.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Dec 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 2A1 Pheochromocytoma Neuroblastoma, susceptibility to, 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002816168.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001535189.4 First in ClinVar: Mar 22, 2021 Last updated: Feb 20, 2024	Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1099 of the KIF1B protein (p.Arg1099His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1099 of the KIF1B protein (p.Arg1099His). This variant is present in population databases (rs373663596, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KIF1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1032652). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 25, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002611972.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.R1099H variant (also known as c.3296G>A), located in coding exon 29 of the KIF1B gene, results from a G to A substitution at nucleotide … (more) The p.R1099H variant (also known as c.3296G>A), located in coding exon 29 of the KIF1B gene, results from a G to A substitution at nucleotide position 3296. The arginine at codon 1099 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1099 of the KIF1B protein (p.Arg1099His). This variant is present in population databases (rs373663596, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with KIF1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1032652). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The p.R1099H variant (also known as c.3296G>A), located in coding exon 29 of the KIF1B gene, results from a G to A substitution at nucleotide position 3296. The arginine at codon 1099 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs373663596 ...

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_001365951.3(KIF1B):c.3434G>A (p.Arg1145His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs373663596 ...