Submissions for variant NM_001376.5(DYNC1H1):c.3073C>T (p.Arg1025Trp) (rs777387819)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000719775	SCV000850645	likely benign	History of neurodevelopmental disorder	2017-08-17	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,Does not segregate with disease in family study (genes with incomplete penetrance)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768204	SCV000898655	uncertain significance	Spinal muscular atrophy, lower extremity predominant 1, autosomal dominant; Charcot-Marie-Tooth disease, axonal, type 2O; Mental retardation, autosomal dominant 13	2018-01-09	criteria provided, single submitter	clinical testing	DYNC1H1 NM_001376.4 exon 12 p.Arg1025Trp (c.3073C>T): This variant has not been reported in the literature but is present in 16/34420 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs777387819). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV000616278	SCV000723310	likely benign	not specified	2018-01-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000693393	SCV000821261	uncertain significance	Charcot-Marie-Tooth disease, axonal, type 2O	2018-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 1025 of the DYNC1H1 protein (p.Arg1025Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs777387819, ExAC 0.05%). This variant has not been reported in the literature in individuals with DYNC1H1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly 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.