ClinVar Miner

Submissions for variant NM_004082.5(DCTN1):c.638C>T (p.Pro213Leu)

dbSNP: rs754827026
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000700467 SCV000829224 uncertain significance Amyotrophic lateral sclerosis type 1; Perry syndrome; Neuronopathy, distal hereditary motor, type 7B 2022-05-28 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 577659). This variant has not been reported in the literature in individuals affected with DCTN1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 213 of the DCTN1 protein (p.Pro213Leu).
Neuberg Centre For Genomic Medicine, NCGM RCV003388594 SCV004100456 uncertain significance Amyotrophic lateral sclerosis type 1 criteria provided, single submitter clinical testing The missense variant p.P213L in DCTN1 (NM_004082.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. Although the variant is present at 0.0011% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.P213L variant is novel (not in any individuals) in 1000 Genomes. This variant was found in ClinVar with a classification of Uncertain Significance. There is a moderate physicochemical difference between proline and leucine. The p.P213L missense variant is predicted to be damaging by both SIFT and PolyPhen2. The proline residue at codon 213 of DCTN1 is conserved in all mammalian species. The nucleotide c.638 in DCTN1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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