Submissions for variant NM_004082.5(DCTN1):c.2002C>T (p.His668Tyr)

gnomAD frequency: 0.00006  dbSNP: rs764443534

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000392721	SCV000432025	likely benign	Perry syndrome	2018-01-13	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	RCV000308445	SCV000432026	uncertain significance	Neuronopathy, distal hereditary motor, type 7B	2018-01-13	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696804	SCV000825383	uncertain significance	Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 668 of the DCTN1 protein (p.His668Tyr). This variant is present in population databases (rs764443534, gnomAD 0.009%). This missense change has been observed in individual(s) with sporadic amyotrophic lateral sclerosis (PMID: 25299611). This variant is also known as p.His534Tyr. ClinVar contains an entry for this variant (Variation ID: 337085). 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 expected to disrupt DCTN1 protein function with a positive predictive value of 80%. 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	RCV002418203	SCV002721701	likely benign	Inborn genetic diseases	2024-01-24	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	RCV003969969	SCV004779400	uncertain significance	DCTN1-related disorder	2023-12-21	criteria provided, single submitter	clinical testing	The DCTN1 c.2002C>T variant is predicted to result in the amino acid substitution p.His668Tyr. This variant, reported as NM_023019.3:c.1600C>T (p.His534Tyr) using a different transcript, was reported in an individual with sporadic amyotrophic lateral sclerosis (Couthouis et al. 2014. PubMed ID: 25299611). Family or functional studies were not reported to help assess the pathogenicity of this variant. This variant is reported in 0.0093% 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.
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000392721	SCV004174774	uncertain significance	Perry syndrome	2016-01-06	no assertion criteria provided	literature only