Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Hudson |
RCV000033152 | SCV000537217 | uncertain significance | Autosomal dominant Charcot-Marie-Tooth disease type 2W | 2024-01-04 | criteria provided, single submitter | research | |
Center for Pediatric Genomic Medicine, |
RCV000514458 | SCV000609999 | uncertain significance | not provided | 2017-08-30 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000650143 | SCV000771980 | uncertain significance | Usher syndrome type 3B | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 137 of the HARS protein (p.Arg137Gln). This variant is present in population databases (rs191391414, gnomAD 0.02%). This missense change has been observed in individual(s) with HARS-related conditions (PMID: 22930593, 27353947, 29790872). ClinVar contains an entry for this variant (Variation ID: 40062). 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 HARS protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HARS function (PMID: 22930593, 32543048). 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. |
Gene |
RCV000514458 | SCV001785908 | uncertain significance | not provided | 2022-10-04 | criteria provided, single submitter | clinical testing | Reported as a heterozygous variant in an individual with peripheral neuropathy (Vester et al., 2013); Reported with a variant on the opposite allele (in trans) in a patient with Usher syndrome in published literature (Tiwari et al., 2016); Published functional studies demonstrate the R137Q variant reduces neurite outgrowth as a result of decreased protein synthesis (Mullen et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23465884, 26072516, 29790872, 27353947, 33236345, 24917879, 23913540, 27876679, 32940403, 22930593, 29288497, 32372680, 32543048) |
Mendelics | RCV002247415 | SCV002517167 | uncertain significance | not specified | 2022-05-04 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002460895 | SCV002755246 | uncertain significance | Inborn genetic diseases | 2019-10-30 | criteria provided, single submitter | clinical testing | The p.R137Q variant (also known as c.410G>A), located in coding exon 5 of the HARS gene, results from a G to A substitution at nucleotide position 410. The arginine at codon 137 is replaced by glutamine, an amino acid with highly similar properties. Based on data from gnomAD, the A allele has an overall frequency of approximately 0.007% (18/251332) total alleles studied. The highest observed frequency was 0.015% (17/113684) of non-Finnish European alleles, which makes it unlikely to be pathogenic. However, this variant has been reported in an affected patient (Vester A et al. Hum. Mutat., 2013 Jan;34:191-9) and a possibly affected patient (Thompson ML et al. Genet. Med., 2018 12;20:1635-1643). Additionally, functional studies were performed that suggested this variant may lack full protein function and may affect commissural neuron out-growth when over-expressed in C. elegans (Vester A et al. Hum. Mutat., 2013 Jan;34:191-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. |
OMIM | RCV000033152 | SCV000056934 | pathogenic | Autosomal dominant Charcot-Marie-Tooth disease type 2W | 2013-01-01 | flagged submission | literature only | |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000514458 | SCV001979554 | pathogenic | not provided | flagged submission | clinical testing | ||
Clinical Genetics DNA and cytogenetics Diagnostics Lab, |
RCV000514458 | SCV001979964 | likely pathogenic | not provided | flagged submission | clinical testing | ||
Clinical Genetics, |
RCV000514458 | SCV002034354 | likely pathogenic | not provided | flagged submission | clinical testing |