VCV000245638.13 - ClinVar

NM_001136472.2(LITAF):c.478C>T (p.Arg160Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(5)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001136472.2(LITAF):c.478C>T (p.Arg160Cys)

Variation ID: 245638 Accession: VCV000245638.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.13 16: 11549645 (GRCh38) [ NCBI UCSC ] 16: 11643501 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 25, 2016	May 1, 2024	Dec 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001136472.2:c.478C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001129944.1:p.Arg160Cys	missense
NM_001136473.1:c.*117C>T		3 prime UTR
NM_004862.4:c.478C>T	NP_004853.2:p.Arg160Cys	missense
NR_024320.2:n.612C>T		non-coding transcript variant
NC_000016.10:g.11549645G>A
NC_000016.9:g.11643501G>A
NG_009008.1:g.42306C>T
LRG_253:g.42306C>T
LRG_253t1:c.*117C>T

... more HGVS ... less HGVS

Protein change

R160C

Other names

Canonical SPDI

NC_000016.10:11549644:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD) 0.00002

Links

ClinGen: CA7904008 dbSNP: rs748017885 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LITAF		No evidence available	No evidence available	GRCh38 GRCh37	284	315

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 14, 2023	RCV000236601.3
Charcot-Marie-Tooth disease type 1C	Likely pathogenic (1)	criteria provided, single submitter	Dec 6, 2023	RCV001218448.9
Charcot-Marie-Tooth disease	Uncertain significance (1)	criteria provided, single submitter	-	RCV001173621.1
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Nov 6, 2019	RCV002327154.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 10, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000292598.10 First in ClinVar: Jul 25, 2016 Last updated: Jul 25, 2016	Comment: The R160C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not … (more) The R160C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R160C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001336722.1 First in ClinVar: Jun 14, 2020 Last updated: Jun 14, 2020
Uncertain significance (Jul 14, 2023)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV004229544.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Publications: PubMed (2) PubMed: 28211240‚ 25614874 Comment: Available data are insufficient to determine the clinical significance of the variant at this time. This variant is statistically more frequent in the patient population … (more) Available data are insufficient to determine the clinical significance of the variant at this time. This variant is statistically more frequent in the patient population than in the general population, which is weak evidence this variant may be disease causing. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has been seen where an alternate explanation for disease was also identified, suggesting this variant may not cause disease. Computational tools disagree on the variant's effect on normal protein function. (less)
Likely pathogenic (Dec 06, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 1C Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001390330.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 28211240‚ 32376792 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 160 of the LITAF protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 160 of the LITAF protein (p.Arg160Cys). This variant is present in population databases (rs748017885, gnomAD 0.0009%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 28211240, 32376792; Invitae). ClinVar contains an entry for this variant (Variation ID: 245638). 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 tolerated. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Uncertain significance (Nov 06, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002634363.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 28211240 Comment: The p.R160C variant (also known as c.478C>T), located in coding exon 3 of the LITAF gene, results from a C to T substitution at nucleotide … (more) The p.R160C variant (also known as c.478C>T), located in coding exon 3 of the LITAF gene, results from a C to T substitution at nucleotide position 478. The arginine at codon 160 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in five individuals from three French families with features of Charcot-Marie-Tooth disorder. Two of these unrelated individuals also had another LITAF variant of uncertain significance identified (Guimarães-Costa R et al. Eur. J. Neurol., 2017 03;24:530-538). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The R160C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R160C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.

Comment:

Available data are insufficient to determine the clinical significance of the variant at this time. This variant is statistically more frequent in the patient population than in the general population, which is weak evidence this variant may be disease causing. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has been seen where an alternate explanation for disease was also identified, suggesting this variant may not cause disease. Computational tools disagree on the variant's effect on normal protein function.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 160 of the LITAF protein (p.Arg160Cys). This variant is present in population databases (rs748017885, gnomAD 0.0009%). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 28211240, 32376792; Invitae). ClinVar contains an entry for this variant (Variation ID: 245638). 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 tolerated. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

The p.R160C variant (also known as c.478C>T), located in coding exon 3 of the LITAF gene, results from a C to T substitution at nucleotide position 478. The arginine at codon 160 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in five individuals from three French families with features of Charcot-Marie-Tooth disorder. Two of these unrelated individuals also had another LITAF variant of uncertain significance identified (Guimarães-Costa R et al. Eur. J. Neurol., 2017 03;24:530-538). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comprehensive genetic sequence and copy number analysis for Charcot-Marie-Tooth disease in a Canadian cohort of 2517 patients.	Volodarsky M	Journal of medical genetics	2021	PMID: 32376792
Phenotypic spectrum of Charcot-Marie-Tooth disease due to LITAF/SIMPLE mutations: a study of 18 patients.	Guimarães-Costa R	European journal of neurology	2017	PMID: 28211240
The allelic spectrum of Charcot-Marie-Tooth disease in over 17,000 individuals with neuropathy.	DiVincenzo C	Molecular genetics & genomic medicine	2014	PMID: 25614874

Text-mined citations for rs748017885 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001136472.2(LITAF):c.478C>T (p.Arg160Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs748017885 ...