Submissions for variant NM_001376.5(DYNC1H1):c.5885G>A (p.Arg1962His)

dbSNP: rs1057518287

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414412	SCV000491791	likely pathogenic	not provided	2016-11-11	criteria provided, single submitter	clinical testing	The R1962H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species, and different missense variants in the same residue (R1962C, R1962L) have been reported in the Human Gene Mutation Database in association with DYNC1H1-related disorders (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R1962H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Fulgent Genetics, Fulgent Genetics	RCV000762920	SCV000893335	likely pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures; Charcot-Marie-Tooth disease axonal type 2O; Intellectual disability, autosomal dominant 13	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001267572	SCV001445754	likely pathogenic	Inborn genetic diseases	2018-03-23	criteria provided, single submitter	clinical testing	The p.R1962H variant (also known as c.5885G>A), located in coding exon 29 of the DYNC1H1 gene, results from a G to A substitution at nucleotide position 5885. The arginine at codon 1962 is replaced by histidine, an amino acid with highly similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of DYNC1H1-related neurological disorder (Ambry internal data). Internal structural analysis indicates this variant to be disruptive to ATP binding (Ambry internal data; Zhang K et al. Cell, 2017 Jun;169:1303-1314.e18). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Revvity Omics, Revvity	RCV000414412	SCV002017348	likely pathogenic	not provided	2019-10-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861429	SCV002304207	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2023-01-10	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC1H1 protein function. ClinVar contains an entry for this variant (Variation ID: 373213). This missense change has been observed in individual(s) with clinical features of DYNC1H1-related conditions (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1962 of the DYNC1H1 protein (p.Arg1962His). This variant disrupts the p.Arg1962 amino acid residue in DYNC1H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23603762, 28196890, 29314763). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.