Submissions for variant NM_004082.5(DCTN1):c.2353C>T (p.Arg785Trp)

gnomAD frequency: 0.00010  dbSNP: rs121909344

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644476	SCV000766174	uncertain significance	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 785 of the DCTN1 protein (p.Arg785Trp). This variant is present in population databases (rs121909344, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with myotrophic lateral sclerosis (ALS) (PMID: 15326253, 19506225). ClinVar contains an entry for this variant (Variation ID: 8404). 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. 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.
Fulgent Genetics, Fulgent Genetics	RCV000644476	SCV000897052	uncertain significance	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000986781	SCV001135904	uncertain significance	Amyotrophic lateral sclerosis type 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001140673	SCV001300954	uncertain significance	Neuronopathy, distal hereditary motor, type 7B	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001140674	SCV001300955	uncertain significance	Perry syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Ambry Genetics	RCV002444424	SCV002734453	likely benign	Inborn genetic diseases	2021-07-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV001572734	SCV003834294	uncertain significance	not provided	2022-01-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952351	SCV004771395	likely benign	DCTN1-related disorder	2022-08-24	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GeneDx	RCV001572734	SCV005324932	uncertain significance	not provided	2023-05-15	criteria provided, single submitter	clinical testing	Reported previously in a patient with apparently sporadic ALS; however, no further clinical or family history information was provided (Mehta et al., 2019); Reported previously as a variant of uncertain significance in a patient with ALS; however, no further clinical or segregation information was provided (Shepheard et al., 2021); Reported previously in two siblings with probable ALS (one with upper limb onset and one with bulbar onset), and also seen in two unaffected family members (Mnch et al., 2004); Reported previously in a patient with ALS (further clinical information not provided) and in one control sample (Morgan et al., 2017); Published functional studies show that this variant does not have major differences in cell morphology (Stockmann et al., 2013; Dixit R et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23447461, 23143281, 33924373, 20349096, 17911166, 31291987, 28235672, 28625595, 16765570, 17593875, 37168679, 19506225, 28792508, 26662454, 25025039, 25109764, 30270202, 33589474, 15326253, 28430856, 18812314)
OMIM	RCV000008912	SCV000029122	risk factor	Amyotrophic lateral sclerosis, susceptibility to	2004-08-24	no assertion criteria provided	literature only
Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust	RCV000144867	SCV000172138	uncertain significance	Charcot-Marie-Tooth disease	2013-11-01	no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001572734	SCV001797551	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001572734	SCV001971475	uncertain significance	not provided		no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium Ii, University Of Miami	RCV001140674	SCV004174410	uncertain significance	Perry syndrome	2016-01-06	no assertion criteria provided	literature only