ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.2327C>T (p.Pro776Leu) (rs1057518083)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413532 SCV000491475 pathogenic not provided 2018-09-04 criteria provided, single submitter clinical testing The P776L pathogenic variant in the DYNC1H1 gene has been reported previously as a de novo variant in two unrelated families with features of DYNC1H1-related disorder (Ding et al., 2016; Beecroft et al., 2017). The P776L variant is not observed in large population cohorts (Lek et al., 2016). The P776L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This variant occur within the dimerization domain in the stem domain (Peeters et al., 2015). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P776L as a pathogenic variant.
Undiagnosed Diseases Network,NIH RCV000625972 SCV000746573 pathogenic Spinal muscular atrophy, lower extremity predominant 1, autosomal dominant 2018-03-16 criteria provided, single submitter clinical testing The c.2327C>T variant in the DYNC1H1 gene has been reported previously (PMCID:4742772). The patient and his 2 similarly affected identical twin brothers were found to carry the variant. The father was mosaic for this variant with mild symptoms.
Invitae RCV000809340 SCV000949489 pathogenic Charcot-Marie-Tooth disease, axonal, type 2O 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 776 of the DYNC1H1 protein (p.Pro776Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with lower extremity predominant spinal muscular atrophy (PMID: 26846447, 28554554). ClinVar contains an entry for this variant (Variation ID: 372934). 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"). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000413532 SCV001447473 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing

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