ClinVar Miner

Submissions for variant NM_002109.6(HARS1):c.410G>A (p.Arg137Gln)

gnomAD frequency: 0.00010  dbSNP: rs191391414
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology 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, Children's Mercy Hospital and Clinics 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.
GeneDx 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, Radboudumc and MUMC+ RCV000514458 SCV001979554 pathogenic not provided flagged submission clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000514458 SCV001979964 likely pathogenic not provided flagged submission clinical testing
Clinical Genetics, Academic Medical Center RCV000514458 SCV002034354 likely pathogenic not provided flagged submission clinical testing

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