rs672601371

Variant names:

• chr2-240783791-A-G
• rs672601371
• NM_001244008.2:c.746T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-240783791-A-G
• chr2-240783791-A-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001244008.2(KIF1A):​c.746T>C​(p.Leu249Pro) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L249M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.04
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• hereditary spastic paraplegia 30

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PEHO syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001244008.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-240783792-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3753714.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-240783791-A-G is Pathogenic according to our data. Variant chr2-240783791-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 986214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.746T>C	p.Leu249Pro	missense_variant	Exon 8 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.746T>C	p.Leu249Pro	missense_variant	Exon 8 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Aug 29, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, autosomal dominant 9 Pathogenic:1

Oct 21, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu249Pro variant in KIF1A has been reported as de novo through trio WES in an individual with features associated with KIF1A-related neurological disorder (KAND), such as severe developmental delay, cerebellar ataxia and atrophy on MRI, spastic paraparesis, and eye findings. The individual also carried a de novo duplication of 22q11.23 that is known to demonstrate variable expression and incomplete penetrance (Demily 2018, PMID: 29589274). The p.Leu249Pro variant was also confirmed to be de novo through trio whole genome sequencing in a young woman with developmental delay, seizures, hypotonia, intellectual disability, cerebellar atrophy, and cortical visual impairment by the Broad Institute Rare Genomes Project. It was absent from large population studies. Another variant involving this codon (p.Leu249Gln) has been identified in other individuals with KIF1A-related neurological disorder (ClinVar variation ID 162061) suggesting that changes at this codon are not tolerated. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The number of missense variants reported in this region of the KIF1A gene in the general population is lower than expected, suggesting that a missense variant in this region may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant KIF1A-related neurological disorder. ACMG/AMP Criteria applied: PS2, PM2_Supporting, PM5_Supporting, PP2, PP3 -

not provided Pathogenic:1

Sep 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26125038, 21820098, 21376300, 29589274) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.0	H;H;.;.;.;.;.;H;.;.;.;H;.
PhyloP100		9.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.7	.;D;D;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;D;.
Vest4		0.99, 0.99
MutPred		0.95		Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);Loss of stability (P = 0.0104);
MVP		1.0
MPC		3.1
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.96
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs672601371; hg19: chr2-241723208;