NM_001136472.2(LITAF):c.268C>T (p.Arg90Cys) AND Charcot-Marie-Tooth disease type 1C

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 14, 2023
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:: RCV000794470.14

Allele description [Variation Report for NM_001136472.2(LITAF):c.268C>T (p.Arg90Cys)]

NM_001136472.2(LITAF):c.268C>T (p.Arg90Cys)

Gene:

LITAF:lipopolysaccharide induced TNF factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16p13.13

Genomic location:

Preferred name:

NM_001136472.2(LITAF):c.268C>T (p.Arg90Cys)

HGVS:

NC_000016.10:g.11553642G>A
NG_009008.1:g.38309C>T
NM_001136472.2:c.268C>TMANE SELECT
NM_001136473.1:c.268C>T
NM_004862.4:c.268C>T
NP_001129944.1:p.Arg90Cys
NP_001129945.1:p.Arg90Cys
NP_004853.2:p.Arg90Cys
NP_004853.2:p.Arg90Cys
LRG_253t1:c.268C>T
LRG_253:g.38309C>T
LRG_253p1:p.Arg90Cys
NC_000016.9:g.11647498G>A
NM_004862.3:c.268C>T
NR_024320.2:n.402C>T

Protein change:

R90C

Links:

dbSNP: rs375665454

NCBI 1000 Genomes Browser:

rs375665454

Molecular consequence:

NM_001136472.2:c.268C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001136473.1:c.268C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004862.4:c.268C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_024320.2:n.402C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Charcot-Marie-Tooth disease type 1C
Synonyms:: CMT, SLOW NERVE CONDUCTION TYPE C; HMSN IC; CMT 1C; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010995; MedGen: C0270913; Orphanet: 101083; OMIM: 601098

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bckdhb branched chain keto acid dehydrogenase E1 subunit beta [Danio rerio]
bckdhb branched chain keto acid dehydrogenase E1 subunit beta [Danio rerio]
Gene ID:569980

Gene
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Gene
Profile neighbors for GEO Profiles (Select 113389124) (199)
GEO Profiles
PMC Links for Gene (Select 3239) (44)
PMC
Phormidium autumnale CCALA 850 16S ribosomal RNA gene and 16S-23S ribosomal RNA ...
Phormidium autumnale CCALA 850 16S ribosomal RNA gene and 16S-23S ribosomal RNA intergenic spacer, partial sequence
gi|508083431|gb|KC633999.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000933881	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 14, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32376792, 28492532
SCV002506293	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Feb 10, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000933881

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 14, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002506293

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Uncertain significance
(Feb 10, 2022)

germline

clinical testing

Citation Link

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

Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.

Volodarsky M, Kerkhof J, Stuart A, Levy M, Brady LI, Tarnopolsky M, Lin H, Ainsworth P, Sadikovic B.

J Med Genet. 2021 Apr;58(4):284-288. doi: 10.1136/jmedgenet-2019-106641. Epub 2020 May 6.

PubMed [citation]

PMID:: 32376792

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000933881.6

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

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 90 of the LITAF protein (p.Arg90Cys). This variant is present in population databases (rs375665454, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 641266). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002506293.2

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

Description

The LITAF c.268C>T; p.Arg90Cys variant (rs375665454) is reported in the literature in an individual with Charcot-Marie-Tooth (CMT) disease (Volodarsky 2021), and it is also reported in ClinVar (Variation ID: 641266). This variant is found in the general population with an overall allele frequency of 0.009% (26/282380 alleles) in the Genome Aggregation Database. The arginine at codon 90 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.656). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Volodarsky M et al. Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients. J Med Genet. 2021 Apr;58(4):284-288. PMID: 32376792.

#	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: Sep 29, 2024

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