Submissions for variant NM_004082.5(DCTN1):c.2551C>G (p.Leu851Val)

gnomAD frequency: 0.00006  dbSNP: rs72659379

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810084	SCV000950271	uncertain significance	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2023-06-22	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 654179). This missense change has been observed in individual(s) with parkinsonism (PMID: 27132499). This variant is present in population databases (rs72659379, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 851 of the DCTN1 protein (p.Leu851Val).
Ambry Genetics	RCV002440741	SCV002745092	likely benign	Inborn genetic diseases	2021-08-17	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.
CeGaT Center for Human Genetics Tuebingen	RCV004721629	SCV005329731	uncertain significance	not provided	2024-08-01	criteria provided, single submitter	clinical testing	DCTN1: PM2
PreventionGenetics, part of Exact Sciences	RCV004745603	SCV005357979	uncertain significance	DCTN1-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The DCTN1 c.2551C>G variant is predicted to result in the amino acid substitution p.Leu851Val. This variant has been reported in three individuals with parkinsonism; however, pathogenicity was not established with functional or segregation analysis (Gustavsson et al. 2016. PubMed ID: 27132499). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.