VCV000476778.21 - ClinVar

NM_001365951.3(KIF1B):c.1594C>G (p.Pro532Ala)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001365951.3(KIF1B):c.1594C>G (p.Pro532Ala)

Variation ID: 476778 Accession: VCV000476778.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.22 1: 10295089 (GRCh38) [ NCBI UCSC ] 1: 10355147 (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 26, 2017	Oct 20, 2024	Jan 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001365951.3:c.1594C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001352880.1:p.Pro532Ala	missense
NM_001365952.1:c.1594C>G	NP_001352881.1:p.Pro532Ala	missense
NM_001365953.1:c.1456C>G	NP_001352882.1:p.Pro486Ala	missense
NM_015074.3:c.1456C>G	NP_055889.2:p.Pro486Ala	missense
NM_183416.4:c.1456C>G	NP_904325.2:p.Pro486Ala	missense
NC_000001.11:g.10295089C>G
NC_000001.10:g.10355147C>G
NG_008069.1:g.89384C>G
LRG_252:g.89384C>G
LRG_252t1:c.1456C>G	LRG_252p1:p.Pro486Ala
LRG_252t2:c.1594C>G	LRG_252p2:p.Pro532Ala

... more HGVS ... less HGVS

Protein change

P486A, P532A

Other names

Canonical SPDI

NC_000001.11:10295088:C: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.

0.00020 (G)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00013

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00025

Links

ClinGen: CA581032 dbSNP: rs201500946 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.
Charcot-Marie-Tooth disease type 2	Uncertain significance (1)	criteria provided, single submitter	Jan 20, 2024	RCV000527411.6
Charcot-Marie-Tooth disease	Uncertain significance (1)	criteria provided, single submitter	-	RCV001173593.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Jul 1, 2023	RCV003133359.12
KIF1B-related disorder	Uncertain significance (1)	no assertion criteria provided	Jul 17, 2024	RCV004742497.1
not specified	Likely benign (1)	criteria provided, single submitter	Jun 25, 2020	RCV004024379.1
Charcot-Marie-Tooth disease type 2A1	Uncertain significance (1)	criteria provided, single submitter	Jul 23, 2019	RCV003485606.2

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001336692.1 First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020
Uncertain significance (Jul 23, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease type 2A1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003814565.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jan 20, 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: SCV000657735.5 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 32376792 Comment: This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 486 of the KIF1B protein (p.Pro486Ala). … (more) This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 486 of the KIF1B protein (p.Pro486Ala). This variant is present in population databases (rs201500946, gnomAD 0.03%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 476778). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF1B protein function. 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)
Likely benign (Jun 25, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002695888.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Jul 01, 2023)	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: SCV004032550.11 First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024	Comment: KIF1B: PP3 Number of individuals with the variant: 1
Uncertain significance (Jul 17, 2024)	no assertion criteria provided Method: clinical testing	KIF1B-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005350532.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The KIF1B c.1456C>G variant is predicted to result in the amino acid substitution p.Pro486Ala. This variant has been reported in two individuals with Charcot-Marie-Tooth disease … (more) The KIF1B c.1456C>G variant is predicted to result in the amino acid substitution p.Pro486Ala. This variant has been reported in two individuals with Charcot-Marie-Tooth disease (Supplementary Table 2. Volodarsky et al. 2021. PubMed ID: 32376792). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD, which may be too common to be a primary cause of disease. This variant has conflicting interpretations in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/476778/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 486 of the KIF1B protein (p.Pro486Ala). This variant is present in population databases (rs201500946, gnomAD 0.03%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 476778). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF1B protein function. 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:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

The KIF1B c.1456C>G variant is predicted to result in the amino acid substitution p.Pro486Ala. This variant has been reported in two individuals with Charcot-Marie-Tooth disease (Supplementary Table 2. Volodarsky et al. 2021. PubMed ID: 32376792). This variant is reported in 0.028% of alleles in individuals of Latino descent in gnomAD, which may be too common to be a primary cause of disease. This variant has conflicting interpretations in ClinVar ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/476778/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.	Volodarsky M	Journal of medical genetics	2021	PMID: 32376792

Text-mined citations for rs201500946 ...

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.1594C>G (p.Pro532Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201500946 ...