2-240783780-C-T

Position:

• chr2-240783780-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001244008.2(KIF1A):​c.757G>A​(p.Glu253Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.67

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]

KIF1A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ 5.1579 (greater than the threshold 3.09). Trascript score misZ 5.0191 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 2-240783780-C-T is Pathogenic according to our data. Variant chr2-240783780-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 162059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.757G>A	p.Glu253Lys	missense_variant	8/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.757G>A	p.Glu253Lys	missense_variant	8/49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1436094 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 711800

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	CHU Sainte-Justine Research Center, University of Montreal	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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 glutamic acid to lysine. (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 (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been found de novo in at least five individuals with syndromic intellectual disability or developmental delay (PMID: 25852444, 26125038, 25265257, 32096284). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2022	Published functional studies demonstrate that this variant results in a protein with no motility that acts in a dominant-negative manner (Esmaeeli Nieh et al., 2015; Boyle et al., 2021); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25265257, 26486474, 25852444, 30385166, 28333917, 26125038, 28332297, 25585697, 25326635, 32096284, 31216405, 32978145, 21376300, 33880452, 31394400, 34916088) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 24, 2021	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 18, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu253 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KIF1A function (PMID: 25265257). 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) performed at Invitae indicates that this missense variant is expected to disrupt KIF1A protein function. ClinVar contains an entry for this variant (Variation ID: 162059). This missense change has been observed in individual(s) with autosomal dominant KIF1A-related conditions (PMID: 25265257). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 253 of the KIF1A protein (p.Glu253Lys). -

Hereditary spastic paraplegia 30 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.757G>A;p.(Glu253Lys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 162059; OMIM: 601255.0007; PMID: 32096284; 30385166; 26125038) -; 25265257) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 25265257) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (kinesin motor domain) - PM1. This variant is not present in population databases (rs672601369, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 32096284; 30385166; 26125038) - PM6. Missense variant in KIF1A that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	4.6	H;H;.;.;.;.;.;H;.;.;.;H;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.2	.;D;D;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	.;D;D;.;.;.;.;.;.;.;.;D;.
Sift4G	Uncertain	0.0020	.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen		0.99	D;.;.;.;.;.;.;D;.;.;.;P;.
Vest4		0.98, 0.99
MutPred		0.92		Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.87
gMVP		1.0

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: rs672601369; hg19: chr2-241723197;