Submissions for variant NM_004082.5(DCTN1):c.3302G>A (p.Arg1101Lys)

gnomAD frequency: 0.00002  dbSNP: rs121909345

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001202903	SCV001374038	uncertain significance	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2024-09-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1101 of the DCTN1 protein (p.Arg1101Lys). This variant is present in population databases (rs121909345, gnomAD 0.006%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis and frontotemporal dementia (PMID: 16240349). ClinVar contains an entry for this variant (Variation ID: 8405). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DCTN1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect DCTN1 function (PMID: 18812314, 23143281). 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.
Ambry Genetics	RCV002453250	SCV002612121	uncertain significance	Inborn genetic diseases	2021-08-03	criteria provided, single submitter	clinical testing	The p.R1101K variant (also known as c.3302G>A), located in coding exon 28 of the DCTN1 gene, results from a G to A substitution at nucleotide position 3302. The arginine at codon 1101 is replaced by lysine, an amino acid with highly similar properties. This variant was identified in the heterozygous state in a pair of siblings, one of whom had amyotrophic lateral sclerosis (ALS) and one of whom had frontotemporal dementia (FTD) (Münch C et al. Ann Neurol, 2005 Nov;58:777-80). In vitro experimental studies show that this alteration does not significantly impact protein function (Dixit R et al. J Biol Chem, 2008 Nov;283:33611-9; Stockmann M et al. J Neural Transm (Vienna), 2013 May;120:785-98). This amino acid position is well conserved in available vertebrate species; however, lysine is the reference amino acid in other 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700205	SCV005203393	uncertain significance	not specified	2024-07-18	criteria provided, single submitter	clinical testing	Variant summary: DCTN1 c.3302G>A (p.Arg1101Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 249326 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3302G>A has been reported in the literature as heterozygous genotype in individuals affected with DCTN1-Related amyotrophic lateral sclerosis and frontotemporal dementia (FTD) in two siblings in one family respectively (Munch_2005). These report(s) do not provide unequivocal conclusions about association of the variant with DCTN1-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Stockmann_2013). The following publications have been ascertained in the context of this evaluation (PMID: 16240349, 23143281). ClinVar contains an entry for this variant (Variation ID: 8405). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM	RCV000008913	SCV000029123	risk factor	Amyotrophic lateral sclerosis, susceptibility to	2005-11-01	no assertion criteria provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003447082	SCV004174432	uncertain significance	Perry syndrome	2016-01-06	no assertion criteria provided	literature only