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

gnomAD frequency: 0.00010  dbSNP: rs191391414

Total submissions: 10

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000650143	SCV000771980	uncertain significance	Usher syndrome type 3B	2024-11-24	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, 36964972). This variant is also known as c.290G>A (p.Arg97Gln). ClinVar contains an entry for this variant (Variation ID: 40062). 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 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	RCV002247415	SCV002755246	uncertain significance	not specified	2023-06-05	criteria provided, single submitter	clinical testing	The c.410G>A (p.R137Q) alteration is located in exon 5 (coding exon 5) of the HARS gene. This alteration results from a G to A substitution at nucleotide position 410, causing the arginine (R) at amino acid position 137 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, 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	uncertain significance	not provided	2024-01-02	no assertion criteria provided	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