NM_001244008.2(KIF1A):c.761G>A (p.Arg254Gln) AND Intellectual disability, autosomal dominant 9

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: May 24, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001078149.11

Allele description [Variation Report for NM_001244008.2(KIF1A):c.761G>A (p.Arg254Gln)]

NM_001244008.2(KIF1A):c.761G>A (p.Arg254Gln)

Gene:

KIF1A:kinesin family member 1A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q37.3

Genomic location:

Preferred name:

NM_001244008.2(KIF1A):c.761G>A (p.Arg254Gln)

HGVS:

NC_000002.12:g.240783776C>T
NG_029724.1:g.41432G>A
NM_001244008.2:c.761G>AMANE SELECT
NM_001320705.2:c.761G>A
NM_001330289.2:c.761G>A
NM_001330290.2:c.761G>A
NM_001379631.1:c.761G>A
NM_001379632.1:c.761G>A
NM_001379633.1:c.761G>A
NM_001379634.1:c.761G>A
NM_001379635.1:c.761G>A
NM_001379636.1:c.761G>A
NM_001379637.1:c.761G>A
NM_001379638.1:c.761G>A
NM_001379639.1:c.761G>A
NM_001379640.1:c.761G>A
NM_001379641.1:c.761G>A
NM_001379642.1:c.761G>A
NM_001379645.1:c.761G>A
NM_001379646.1:c.761G>A
NM_001379648.1:c.761G>A
NM_001379649.1:c.761G>A
NM_001379650.1:c.761G>A
NM_001379651.1:c.761G>A
NM_001379653.1:c.761G>A
NM_004321.8:c.761G>A
NP_001230937.1:p.Arg254Gln
NP_001230937.1:p.Arg254Gln
NP_001307634.1:p.Arg254Gln
NP_001317218.1:p.Arg254Gln
NP_001317219.1:p.Arg254Gln
NP_001366560.1:p.Arg254Gln
NP_001366561.1:p.Arg254Gln
NP_001366562.1:p.Arg254Gln
NP_001366563.1:p.Arg254Gln
NP_001366564.1:p.Arg254Gln
NP_001366565.1:p.Arg254Gln
NP_001366566.1:p.Arg254Gln
NP_001366567.1:p.Arg254Gln
NP_001366568.1:p.Arg254Gln
NP_001366569.1:p.Arg254Gln
NP_001366570.1:p.Arg254Gln
NP_001366571.1:p.Arg254Gln
NP_001366574.1:p.Arg254Gln
NP_001366575.1:p.Arg254Gln
NP_001366577.1:p.Arg254Gln
NP_001366578.1:p.Arg254Gln
NP_001366579.1:p.Arg254Gln
NP_001366580.1:p.Arg254Gln
NP_001366582.1:p.Arg254Gln
NP_004312.2:p.Arg254Gln
NP_004312.2:p.Arg254Gln
LRG_367t1:c.761G>A
LRG_367t2:c.761G>A
LRG_367:g.41432G>A
LRG_367p1:p.Arg254Gln
LRG_367p2:p.Arg254Gln
NC_000002.11:g.241723193C>T
NM_001244008.1:c.761G>A
NM_004321.6:c.761G>A
NM_004321.7:c.761G>A

Protein change:

R254Q; ARG254GLN

Links:

OMIM: 601255.0011; dbSNP: rs886041692

NCBI 1000 Genomes Browser:

rs886041692

Molecular consequence:

NM_001244008.2:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320705.2:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330289.2:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001330290.2:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379631.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379632.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379633.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379634.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379635.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379636.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379637.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379638.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379639.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379640.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379641.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379642.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379645.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379646.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379648.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379649.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379650.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379651.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001379653.1:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004321.8:c.761G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Intellectual disability, autosomal dominant 9 (NESCAVS)
Synonyms:: Mental retardation, autosomal dominant 9; NESCAV SYNDROME
Identifiers:: MONDO: MONDO:0013656; MedGen: C5393830; OMIM: 614255

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001244200	OMIM	no assertion criteria provided	Pathogenic (Apr 16, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001426706	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 15, 2020)	unknown	curation	PubMed (2) [See all records that cite these PMIDs] 26354034, 25741868
SCV001428463	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 26, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002548308	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 24, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31616253, 33880452, 26354034, 32746806 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Going Too Far Is the Same as Falling Short(†): Kinesin-3 Family Members in Hereditary Spastic Paraplegia.

Gabrych DR, Lau VZ, Niwa S, Silverman MA.

Front Cell Neurosci. 2019;13:419. doi: 10.3389/fncel.2019.00419. Review.

PubMed [citation]

PMID:: 31616253
PMCID:: PMC6775250

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV001244200.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In an 8-year-old boy (patient 1) with NESCAV syndrome (NESCAVS; 614255), Ohba et al. (2015) identified a de novo heterozygous c.761G-A transition (c.761G-A, NM_001244008.1) in the KIF1A gene, resulting in an arg254-to-gln (R254Q) substitution at a conserved residue in the motor domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 138), Exome Sequencing Project, 1000 Genomes Project, or ExAC databases, or in an in-house database of 575 control exomes. Functional studies of the variant and studies of patient cells were not performed.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From SIB Swiss Institute of Bioinformatics, SCV001426706.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

This variant is interpreted as pathogenic for NESCAV syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); De novo (paternity and maternity confirmed) (PS2); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2); Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (PM5).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001428463.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002548308.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: KIF1A c.761G>A (p.Arg254Gln) results in a conservative amino acid change located in the Kinesin motor domain (IPR001752) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 210076 control chromosomes (gnomAD and publication data). c.761G>A has been reported in the literature in individuals affected with KIF1A-associated neurological disorder (Ohba_2015, Rudenskaya_2020, Boyle_2021), including one de novo occurrence. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In addition, p.Arg254 is close to the ATP binding site of KIF1A and involved in ATP and motor protein binding (CryoEM structure, Boyle_2021). Other missense substitutions at this codon (p.Arg254Pro, p.Arg254Gly and p.Arg254Trp) have been reported in affected individuals and classified as pathogenic/likely pathogenic in ClinVar database, suggesting that this arginine residue is critical for KIF1A protein function. Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=6) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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