ClinVar Miner

Submissions for variant NM_004082.5(DCTN1):c.1480G>A (p.Ala494Thr)

gnomAD frequency: 0.00012  dbSNP: rs113980038
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001349255 SCV001543589 uncertain significance Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B 2023-09-14 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 494 of the DCTN1 protein (p.Ala494Thr). This variant is present in population databases (rs113980038, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 28709720). This variant is also known as p.A457T. 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: 1044931).
Ambry Genetics RCV002395773 SCV002701158 likely benign Inborn genetic diseases 2020-12-08 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.

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