Submissions for variant NM_004082.5(DCTN1):c.1217G>A (p.Arg406Lys)

gnomAD frequency: 0.00001  dbSNP: rs1040712616

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000644459	SCV000766157	uncertain significance	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2023-09-08	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 406 of the DCTN1 protein (p.Arg406Lys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DCTN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 536144). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DCTN1 protein function. 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	RCV002358838	SCV002660408	uncertain significance	Inborn genetic diseases	2020-04-10	criteria provided, single submitter	clinical testing	The p.R406K variant (also known as c.1217G>A), located in coding exon 12 of the DCTN1 gene, results from a G to A substitution at nucleotide position 1217. The arginine at codon 406 is replaced by lysine, an amino acid with highly similar properties. 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.
PreventionGenetics, part of Exact Sciences	RCV003403485	SCV004119396	uncertain significance	DCTN1-related disorder	2023-04-13	criteria provided, single submitter	clinical testing	The DCTN1 c.1217G>A variant is predicted to result in the amino acid substitution p.Arg406Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-74597383-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987642	SCV004804059	uncertain significance	not specified	2024-01-31	criteria provided, single submitter	clinical testing	Variant summary: DCTN1 c.1217G>A (p.Arg406Lys) 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 2.4e-05 in 251248 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1217G>A in individuals affected with DCTN1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 536144). Based on the evidence outlined above, the variant was classified as uncertain significance.