Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000757351 | SCV000885541 | uncertain significance | not provided | 2017-12-12 | criteria provided, single submitter | clinical testing | The p.Arg266His variant (rs765223763) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. It is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD). The arginine at position 266 is weakly conserved considering 12 species (Alamut v2.10) and computational analyses of the effects of the p.Arg266His variant on protein structure and function provide conflicting results (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Arg266His variant with certainty. |
| Labcorp Genetics |
RCV001047038 | SCV001210970 | uncertain significance | Usher syndrome type 3B | 2024-10-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 266 of the HARS protein (p.Arg266His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 618673). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt HARS protein function with a negative predictive value of 80%. 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. |
| Ambry Genetics | RCV003323711 | SCV002755235 | uncertain significance | not specified | 2024-08-27 | criteria provided, single submitter | clinical testing | The c.797G>A (p.R266H) alteration is located in exon 8 (coding exon 8) of the HARS gene. This alteration results from a G to A substitution at nucleotide position 797, causing the arginine (R) at amino acid position 266 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323711 | SCV004029410 | uncertain significance | not specified | 2023-07-21 | criteria provided, single submitter | clinical testing | Variant summary: HARS c.797G>A (p.Arg266His) results in a non-conservative amino acid change located in the Aminoacyl-tRNA synthetase, class II (IPR006195) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.797G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |