NM_006612.6(KIF1C):c.499C>T (p.Arg167Trp) AND Spastic ataxia 2

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 23, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000540072.10

Allele description [Variation Report for NM_006612.6(KIF1C):c.499C>T (p.Arg167Trp)]

NM_006612.6(KIF1C):c.499C>T (p.Arg167Trp)

Gene:

KIF1C:kinesin family member 1C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.2

Genomic location:

Preferred name:

NM_006612.6(KIF1C):c.499C>T (p.Arg167Trp)

HGVS:

NC_000017.11:g.5002533C>T
NG_034137.1:g.9586C>T
NM_006612.6:c.499C>TMANE SELECT
NP_006603.2:p.Arg167Trp
NC_000017.10:g.4905828C>T
NM_006612.5:c.499C>T
p.Arg167Trp

Protein change:

R167W

Links:

dbSNP: rs185479618

NCBI 1000 Genomes Browser:

rs185479618

Molecular consequence:

NM_006612.6:c.499C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Spastic ataxia 2
Synonyms:: Ataxia, spastic, 2, autosomal recessive
Identifiers:: MONDO: MONDO:0012651; MedGen: C1969796; Orphanet: 397946; OMIM: 611302

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000645948	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Aug 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001164347	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 3, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000645948

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Aug 23, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001164347

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 3, 2018)

germline

research

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000645948.4

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001164347.1

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

Description

The heterozygous p.Arg167Trp variant in KIF1C was identified by our study in the compound heterozygous state, along with another VUS, in one individual withspastic ataxia. The p.Arg167Trp variant in KIF1C has not been previously reported in individuals with spastic ataxia but has been identified in 0.04770% (9/18868) of East Asian chromosomes, 0.004163% (1/24022) of African chromosomes, and 0.002906% (1/34416) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs185479618). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg167Trp variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015).

#	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		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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