Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Centre for Mendelian Genomics, |
RCV000414974 | SCV000492853 | likely pathogenic | Myopathy; Pes cavus; Hammertoe; Distal lower limb amyotrophy | 2015-05-11 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000512659 | SCV000608712 | uncertain significance | not provided | 2016-05-01 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000649558 | SCV000771387 | pathogenic | Charcot-Marie-Tooth disease, axonal, type 2O | 2019-09-06 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with cysteine at codon 251 of the DYNC1H1 protein (p.Arg251Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in several individuals affected with spinal muscular atrophy with lower extremity predominant (SMALED) (PMID: 30122514). This variant has also been reported in an individual affected with an abnormality of the nervous system (PMID: 26633542). ClinVar contains an entry for this variant (Variation ID: 374099). 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: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg251His) has been determined to be likely pathogenic (PMID: 26392352, Invitae). This suggests that the arginine residue is critical for DYNC1H1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. |
Ambry Genetics | RCV001266345 | SCV001444519 | likely pathogenic | Inborn genetic diseases | 2019-12-19 | criteria provided, single submitter | clinical testing |