ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.1792C>T (p.Arg598Cys) (rs587780564)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624400 SCV000741139 likely pathogenic Inborn genetic diseases 2015-10-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center for Genetic Medicine Research,Children's National Medical Center RCV000144249 SCV000154972 likely pathogenic Spinal muscular atrophy, lower extremity predominant 1, autosomal dominant 2014-06-10 no assertion criteria provided research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255067 SCV000708036 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762919 SCV000893334 pathogenic Spinal muscular atrophy, lower extremity predominant 1, autosomal dominant; Charcot-Marie-Tooth disease, axonal, type 2O; Mental retardation, autosomal dominant 13 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000255067 SCV000321571 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing The R598C variant in the DYNC1H1 gene has been reported as a de novo pathogenic variant in two unrelated patients with spinal muscular atrophy with lower extremity predominance (Punetha et al., 2015; Strickland et al., 2015). It has also been reported in a large family with autosomal dominant axonal hereditary sensory motor neuropathy (Peeters et al., 2015). Functional analysis demonstrated that the R598C variant results in a protein that shows increased binding to the BICD2 adaptor as compared to wild type (Peeters et al., 2015). The R598C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R598C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is highly conserved across species. Therefore, the presence of R598C is consistent with the diagnosis of a DYNC1H1-related disorder in this individual.
Molecular Neurogenomics lab,VIB Department of Molecular Genetics; University of Antwerp RCV000149555 SCV000191985 pathogenic Hereditary motor and sensory neuropathy 2013-11-20 criteria provided, single submitter research segregates with the phenotype; absent in 179 ethnically matched controls
SIB Swiss Institute of Bioinformatics RCV000755714 SCV000883188 likely pathogenic Charcot-Marie-Tooth disease, axonal, type 2O 2018-10-15 criteria provided, single submitter curation This variant is interpreted as Likely Pathogenic, for Charcot-Marie-Tooth disease axonal type 20, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PS3-Moderate => PS3 downgraded in strength to Moderate ( PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.

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