Submissions for variant NM_004082.5(DCTN1):c.673C>T (p.Arg225Trp)

gnomAD frequency: 0.00004  dbSNP: rs371723224

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000756010	SCV000621906	uncertain significance	not provided	2017-10-23	criteria provided, single submitter	clinical testing	The R225W variant in the DCTN1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The variant is observed in 2/9848 (0.02%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The 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 where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R225W as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644472	SCV000766170	uncertain significance	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2024-01-01	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 225 of the DCTN1 protein (p.Arg225Trp). This variant is present in population databases (rs371723224, gnomAD 0.02%). This missense change has been observed in individual(s) with dementia (PMID: 29525180). ClinVar contains an entry for this variant (Variation ID: 453052). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756010	SCV000883706	uncertain significance	not provided	2017-11-21	criteria provided, single submitter	clinical testing	The p.Arg225Trp variant (rs371723224) has not been reported in the medical literature, nor is it listed in gene-specific variant databases. The p.Arg225Trp variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.004% (identified in 10 out of 246,064 chromosomes). The arginine at codon 225 is highly conserved considering 10 species up to opossum (Alamut software v2.10.0), but computational analyses predict conflicting effects of this variant on protein structure/function (SIFT: damaging, PolyPhen2: benign). Therefore, based on the available information, the clinical significance of the p.Arg225Trp variant cannot be determined with certainty.
Illumina Laboratory Services, Illumina	RCV001137903	SCV001297896	likely benign	Neuronopathy, distal hereditary motor, type 7B	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001137904	SCV001297897	likely benign	Perry syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genetics and Molecular Pathology, SA Pathology	RCV002272277	SCV002556467	likely benign	Parkinsonian disorder	2020-01-17	criteria provided, single submitter	clinical testing	The DCTN1 c.673C>T variant is classified as Likely Benign (BS4, PM2, PP3) This variant does not segregate with disease in this family (BS4).
Ambry Genetics	RCV002527653	SCV003536863	likely benign	Inborn genetic diseases	2021-11-02	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.
PreventionGenetics, part of Exact Sciences	RCV003900094	SCV004717940	uncertain significance	DCTN1-related disorder	2023-11-09	criteria provided, single submitter	clinical testing	The DCTN1 c.673C>T variant is predicted to result in the amino acid substitution p.Arg225Trp. This variant was reported in an individual with a behavioral variant of frontotemporal dementia (Bartoletti-Stella et al 2018. PubMed ID: 29525180, Table 3). This variant is reported in 0.020% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-74598276-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.