VCV002005626.3 - ClinVar

NM_001244008.2(KIF1A):c.961G>A (p.Gly321Ser)

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.

(2)

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
Likely pathogenic(1); Uncertain significance(1)

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.961G>A (p.Gly321Ser)

Variation ID: 2005626 Accession: VCV002005626.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 240774259 (GRCh38) [ NCBI UCSC ] 2: 241713676 (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 8, 2023	Mar 10, 2024	Jan 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001244008.2:c.961G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001230937.1:p.Gly321Ser	missense
NM_001320705.2:c.961G>A	NP_001307634.1:p.Gly321Ser	missense
NM_001330289.2:c.961G>A	NP_001317218.1:p.Gly321Ser	missense
NM_001330290.2:c.961G>A	NP_001317219.1:p.Gly321Ser	missense
NM_001379631.1:c.961G>A	NP_001366560.1:p.Gly321Ser	missense
NM_001379632.1:c.961G>A	NP_001366561.1:p.Gly321Ser	missense
NM_001379633.1:c.961G>A	NP_001366562.1:p.Gly321Ser	missense
NM_001379634.1:c.961G>A	NP_001366563.1:p.Gly321Ser	missense
NM_001379635.1:c.961G>A	NP_001366564.1:p.Gly321Ser	missense
NM_001379636.1:c.961G>A	NP_001366565.1:p.Gly321Ser	missense
NM_001379637.1:c.961G>A	NP_001366566.1:p.Gly321Ser	missense
NM_001379638.1:c.961G>A	NP_001366567.1:p.Gly321Ser	missense
NM_001379639.1:c.961G>A	NP_001366568.1:p.Gly321Ser	missense
NM_001379640.1:c.961G>A	NP_001366569.1:p.Gly321Ser	missense
NM_001379641.1:c.961G>A	NP_001366570.1:p.Gly321Ser	missense
NM_001379642.1:c.961G>A	NP_001366571.1:p.Gly321Ser	missense
NM_001379645.1:c.961G>A	NP_001366574.1:p.Gly321Ser	missense
NM_001379646.1:c.961G>A	NP_001366575.1:p.Gly321Ser	missense
NM_001379648.1:c.961G>A	NP_001366577.1:p.Gly321Ser	missense
NM_001379649.1:c.961G>A	NP_001366578.1:p.Gly321Ser	missense
NM_001379650.1:c.961G>A	NP_001366579.1:p.Gly321Ser	missense
NM_001379651.1:c.961G>A	NP_001366580.1:p.Gly321Ser	missense
NM_001379653.1:c.961G>A	NP_001366582.1:p.Gly321Ser	missense
NM_001379654.1:c.961G>A	NP_001366583.1:p.Gly321Ser	missense
NM_004321.8:c.961G>A	NP_004312.2:p.Gly321Ser	missense
NC_000002.12:g.240774259C>T
NC_000002.11:g.241713676C>T
NG_029724.1:g.50949G>A
LRG_367:g.50949G>A
LRG_367t1:c.961G>A	LRG_367p1:p.Gly321Ser
LRG_367t2:c.961G>A	LRG_367p2:p.Gly321Ser

... more HGVS ... less HGVS

Protein change

G321S

Other names

Canonical SPDI

NC_000002.12:240774258: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.

Links

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	2892	3101

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 30 Intellectual disability, autosomal dominant 9 Neuropathy, hereditary sensory, type 2C	Uncertain significance (1)	criteria provided, single submitter	Oct 3, 2022	RCV002837480.3
Hereditary spastic paraplegia 30	Likely pathogenic (1)	criteria provided, single submitter	Jan 9, 2024	RCV003886585.1

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 03, 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: SCV003206633.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Comment: 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 … (more) 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 321 of the KIF1A protein (p.Gly321Ser). (less)
Likely pathogenic (Jan 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 30 Affected status: yes Allele origin: germline	Human Genetics Bochum, Ruhr University Bochum Accession: SCV004704569.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024	Publications: PubMed (2) PubMed: 34234304‚ 30778698 Comment: ACMG criteria used to clasify this variant: PP3_MOD, PS4_SUP, PM1_SUP, PM2_SUP, PM5_SUP

Comment:

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 321 of the KIF1A protein (p.Gly321Ser).

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
High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.	Benkirane M	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 34234304
Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes.	Elert-Dobkowska E	Neurogenetics	2019	PMID: 30778698

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001244008.2(KIF1A):c.961G>A (p.Gly321Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...