rs587778791

chr2-240757336-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001244008.2(KIF1A):c.2840del(p.Leu947ArgfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000129 in 1,550,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: KIF1A NM_001244008.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.80

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-240757336-CA-C is Pathogenic according to our data. Variant chr2-240757336-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 65859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240757336-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.2840del	p.Leu947ArgfsTer4	frameshift_variant	27/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.2840del	p.Leu947ArgfsTer4	frameshift_variant	27/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000136 AC: 19 AN: 1398358 Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 8 AN XY: 689698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000158

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuropathy, hereditary sensory, type 2C Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 12, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 17, 2020	Variant summary: KIF1A c.2555+1023delT (NM_004321.7) is located in the intron 25 of the KIF1A gene. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 150700 control chromosomes (gnomAD and publication data). The KIF1A gene comprises 47 exons plus some alternatively spliced coding exons and has multiple different transcripts. In one of the alternative transcripts (NM_001244008.1) the variant is predicted to cause a frameshift change (c.2840delT, p.Leu947ArgfsX4). Riviere et al (2011) report c.2840delT, in the homozygous and compound heterozygous state, in 4 different families with multiple individuals affected with Hereditary Sensory And Autonomic Neuropathy Type IIC. They specify the variant is located in the alternatively spliced exon 25b and provide evidence that KIF1A exon-25b-containing isoform is strongly expressed in the nervous system. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Neuropathy, hereditary sensory and autonomic, type 2A Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Nov 23, 2010

- -

KIF1A-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2023

The KIF1A c.2840delT variant is predicted to result in a frameshift and premature protein termination (p.Leu947Argfs*4). This variant may also be described as ENST00000320389.11 c.2555+1023del, and has been reported to be causative for autosomal recessive hereditary sensory and autonomic neuropathy type II in nine patients from four families (Rivière et al. 2011. PubMed ID: 21820098). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in KIF1A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 01, 2023

ClinVar contains an entry for this variant (Variation ID: 65859). This variant is also known as c.2840delT (p.Leu947Argfs*4). This variant has been observed in individual(s) with autosomal recessive hereditary sensory and autonomic neuropathy (PMID: 21820098). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 24 of the KIF1A gene. It does not directly change the encoded amino acid sequence of the KIF1A protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587778791; hg19: chr2-241696753;