ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.6997C>T (p.Leu2333Phe) (rs1131691358)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493383 SCV000581948 uncertain significance not specified 2017-05-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DYNC1H1 gene. The L2333F variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L2333F variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L2333F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001242733 SCV001415841 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2O 2019-10-22 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 2333 of the DYNC1H1 protein (p.Leu2333Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DYNC1H1-related conditions. ClinVar contains an entry for this variant (Variation ID: 429389). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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