Submissions for variant NM_002109.6(HARS1):c.382C>T (p.Arg128Cys)

gnomAD frequency: 0.00031  dbSNP: rs138582560

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540562	SCV000652292	uncertain significance	Usher syndrome type 3B	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 128 of the HARS protein (p.Arg128Cys). This variant is present in population databases (rs138582560, gnomAD 0.05%). 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: 351240). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV001567367	SCV001791032	uncertain significance	not provided	2024-07-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV004021987	SCV002755240	likely benign	not specified	2022-06-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV001567367	SCV004698669	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	HARS1: PM2:Supporting, PP3
Clinical Genetics, Academic Medical Center	RCV001567367	SCV001921092	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001567367	SCV001965601	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001567367	SCV001979327	uncertain significance	not provided		no assertion criteria provided	clinical testing