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

gnomAD frequency: 0.00002  dbSNP: rs748017885

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236601	SCV000292598	uncertain significance	not provided	2015-08-10	criteria provided, single submitter	clinical testing	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.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001173621	SCV001336722	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001218448	SCV001390330	likely pathogenic	Charcot-Marie-Tooth disease type 1C	2025-01-09	criteria provided, single submitter	clinical testing	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: 25614874, 28211240, 32376792; internal data). 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. This variant disrupts the p.Arg160 amino acid residue in LITAF. Other variant(s) that disrupt this residue have been observed in individuals with LITAF-related conditions (PMID: 37868241), which suggests that this may be a clinically significant amino acid residue. 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.
Ambry Genetics	RCV002327154	SCV002634363	uncertain significance	Inborn genetic diseases	2019-11-06	criteria provided, single submitter	clinical testing	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.
Athena Diagnostics	RCV000236601	SCV004229544	uncertain significance	not provided	2023-07-14	criteria provided, single submitter	clinical testing	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001218448	SCV006057276	uncertain significance	Charcot-Marie-Tooth disease type 1C	2020-08-10	criteria provided, single submitter	research