NM_001244008.2(KIF1A):c.760C>T (p.Arg254Trp) AND Intellectual disability, autosomal dominant 9

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: May 22, 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:: RCV000995795.9

Allele description [Variation Report for NM_001244008.2(KIF1A):c.760C>T (p.Arg254Trp)]

NM_001244008.2(KIF1A):c.760C>T (p.Arg254Trp)

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.760C>T (p.Arg254Trp)

HGVS:

NC_000002.12:g.240783777G>A
NG_029724.1:g.41431C>T
NM_001244008.2:c.760C>TMANE SELECT
NM_001320705.2:c.760C>T
NM_001330289.2:c.760C>T
NM_001330290.2:c.760C>T
NM_001379631.1:c.760C>T
NM_001379632.1:c.760C>T
NM_001379633.1:c.760C>T
NM_001379634.1:c.760C>T
NM_001379635.1:c.760C>T
NM_001379636.1:c.760C>T
NM_001379637.1:c.760C>T
NM_001379638.1:c.760C>T
NM_001379639.1:c.760C>T
NM_001379640.1:c.760C>T
NM_001379641.1:c.760C>T
NM_001379642.1:c.760C>T
NM_001379645.1:c.760C>T
NM_001379646.1:c.760C>T
NM_001379648.1:c.760C>T
NM_001379649.1:c.760C>T
NM_001379650.1:c.760C>T
NM_001379651.1:c.760C>T
NM_001379653.1:c.760C>T
NM_004321.8:c.760C>T
NP_001230937.1:p.Arg254Trp
NP_001230937.1:p.Arg254Trp
NP_001307634.1:p.Arg254Trp
NP_001317218.1:p.Arg254Trp
NP_001317219.1:p.Arg254Trp
NP_001366560.1:p.Arg254Trp
NP_001366561.1:p.Arg254Trp
NP_001366562.1:p.Arg254Trp
NP_001366563.1:p.Arg254Trp
NP_001366564.1:p.Arg254Trp
NP_001366565.1:p.Arg254Trp
NP_001366566.1:p.Arg254Trp
NP_001366567.1:p.Arg254Trp
NP_001366568.1:p.Arg254Trp
NP_001366569.1:p.Arg254Trp
NP_001366570.1:p.Arg254Trp
NP_001366571.1:p.Arg254Trp
NP_001366574.1:p.Arg254Trp
NP_001366575.1:p.Arg254Trp
NP_001366577.1:p.Arg254Trp
NP_001366578.1:p.Arg254Trp
NP_001366579.1:p.Arg254Trp
NP_001366580.1:p.Arg254Trp
NP_001366582.1:p.Arg254Trp
NP_004312.2:p.Arg254Trp
NP_004312.2:p.Arg254Trp
LRG_367t1:c.760C>T
LRG_367t2:c.760C>T
LRG_367:g.41431C>T
LRG_367p1:p.Arg254Trp
LRG_367p2:p.Arg254Trp
NC_000002.11:g.241723194G>A
NM_001244008.1:c.760C>T
NM_004321.5:c.760C>T
NM_004321.6:c.760C>T
NM_004321.7:c.760C>T
NM_001224008.1:c.760C>T

Protein change:

R254W; ARG254TRP

Links:

OMIM: 601255.0012; dbSNP: rs879253888

NCBI 1000 Genomes Browser:

rs879253888

Molecular consequence:

NM_001244008.2:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320705.2:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330289.2:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330290.2:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379631.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379632.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379633.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379634.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379635.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379636.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379637.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379638.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379639.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379640.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379641.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379642.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379645.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379646.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379648.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379649.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379650.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379651.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001379653.1:c.760C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004321.8:c.760C>T - 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
SCV001150146	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Jan 30, 2018)	de novo	clinical testing	Citation Link,
SCV001244201	OMIM	no assertion criteria provided	Pathogenic (Apr 16, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001426707	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 15, 2020)	unknown	curation	PubMed (3) [See all records that cite these PMIDs] 26354034, 32096284, 25741868
SCV002521374	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	de novo	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

De novo KIF1A mutations cause intellectual deficit, cerebellar atrophy, lower limb spasticity and visual disturbance.

Ohba C, Haginoya K, Osaka H, Kubota K, Ishiyama A, Hiraide T, Komaki H, Sasaki M, Miyatake S, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Saitsu H, Matsumoto N.

J Hum Genet. 2015 Dec;60(12):739-42. doi: 10.1038/jhg.2015.108. Epub 2015 Sep 10.

PubMed [citation]

PMID:: 26354034

Nemani T, Steel D, Kaliakatsos M, DeVile C, Ververi A, Scott R, Getov S, Sudhakar S, Male A, Mankad K; Genomics England Research Consortium, Muntoni F, Reilly MM, Kurian MA, Carr L, Munot P.

J Peripher Nerv Syst. 2020 Jun;25(2):117-124. doi: 10.1111/jns.12368. Epub 2020 Mar 6.

PubMed [citation]

PMID:: 32096284

See all PubMed Citations (3)

Details of each submission

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001150146.1

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

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

From OMIM, SCV001244201.1

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

Description

In a 27-year-old woman (patient 2) with NESCAV syndrome (NESCAVS; 614255), Ohba et al. (2015) identified a de novo heterozygous c.760C-T transition (c.760C-T, NM_001224008.1) in the KIF1A gene, resulting in an arg254-to-trp (R254W) 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, SCV001426707.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

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); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1 downgraded to supporting); Prevalence in affected individuals statistically increased over controls (PS4 downgraded to supporting).

#	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 3billion, SCV002521374.1

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

Description

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.81; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000245636). Different missense changes at the same codon (p.Arg254Gln, p.Arg254Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000280500, VCV000392042). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Oct 20, 2024

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