ClinVar Miner

Submissions for variant NM_004082.5(DCTN1):c.3557T>C (p.Met1186Thr)

gnomAD frequency: 0.00006  dbSNP: rs145819459
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000694263 SCV000822699 uncertain significance Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B 2023-12-22 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1186 of the DCTN1 protein (p.Met1186Thr). This variant is present in population databases (rs145819459, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DCTN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 572789). 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 with a negative 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001811448 SCV002048800 uncertain significance not provided 2021-09-27 criteria provided, single submitter clinical testing The DCTN1 c.3557T>C, p.Met1186Thr variant (rs145819459), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 572789). This variant is found in the general population with an overall allele frequency of 0.005% (15/275,000 alleles) in the Genome Aggregation Database. The methionine at codon 1186 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.189). Based on the available information, the clinical significance of this variant is uncertain.
Ambry Genetics RCV002458247 SCV002617937 likely benign Inborn genetic diseases 2020-01-13 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.
Fulgent Genetics, Fulgent Genetics RCV000694263 SCV002783357 uncertain significance Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B 2022-02-15 criteria provided, single submitter clinical testing

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