Submissions for variant NM_012208.4(HARS2):c.448C>T (p.Arg150Cys)

gnomAD frequency: 0.00009  dbSNP: rs140540222

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000199285	SCV000251608	uncertain significance	not provided	2022-04-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 34406847, 31827252, 31449985)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223531	SCV000271834	uncertain significance	not specified	2016-05-01	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg150Cys variant in HARS2 has been reported by our laboratory in one individual with hea ring loss who was compound heterozygous for a second variant of uncertain signif icance in the HARS2 gene (this family). This variant has been identified in 6/1 21406 total chromosomes across all populations by the Exome Aggregation Consorti um (ExAC, http://exac.broadinstitute.org; dbSNP rs140540222). Although this vari ant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools suggest that the p.A rg150Cys variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg150Cys variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199285	SCV002177995	pathogenic	not provided	2024-01-20	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 150 of the HARS2 protein (p.Arg150Cys). This variant is present in population databases (rs140540222, gnomAD 0.008%). This missense change has been observed in individuals with clinical features of Perrault syndrome (PMID: 31449985). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214543). 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 HARS2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000782169	SCV000920637	likely pathogenic	Perrault syndrome 2	2019-05-20	no assertion criteria provided	clinical testing	Variant detected as compound heterozygous, together with c.172A>G in three siblings (two girls) with progressive sensorineural hearing impairment. Signs of premature ovarian failure were uncertain due to their young age. Variant detected as compound heterozygous, together with c.980G>A in a girl with progressive sensorineural hearing impairment. Signs of premature ovarian failure were uncertain due to her young age.