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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 13, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001857794.5

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]

Condition(s)

Name:: Hereditary spastic paraplegia 30
Synonyms:: Spastic paraplegia 30, autosomal recessive; SPASTIC PARAPLEGIA 30A, AUTOSOMAL DOMINANT
Identifiers:: MONDO: MONDO:0012476; MedGen: C5235139; Orphanet: 101010; OMIM: 610357

Name:: Neuropathy, hereditary sensory, type 2C
Synonyms:: Hereditary sensory and autonomic neuropathy type IIC
Identifiers:: MONDO: MONDO:0013634; MedGen: C3280168; Orphanet: 970; OMIM: 614213

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
SCV002227442	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 30564185, 26354034, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002227442

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 13, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.

D'Amore A, Tessa A, Casali C, Dotti MT, Filla A, Silvestri G, Antenora A, Astrea G, Barghigiani M, Battini R, Battisti C, Bruno I, Cereda C, Dato C, Di Iorio G, Donadio V, Felicori M, Fini N, Fiorillo C, Gallone S, Gemignani F, Gigli GL, et al.

Front Neurol. 2018;9:981. doi: 10.3389/fneur.2018.00981.

PubMed [citation]

PMID:: 30564185
PMCID:: PMC6289125

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002227442.3

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 254 of the KIF1A protein (p.Arg254Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant hereditary spastic paraplegia (PMID: 26354034, 30564185). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 245636). 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. This variant disrupts the p.Arg254 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26354034). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been 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 20, 2024

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