Submissions for variant NM_012208.4(HARS2):c.172A>G (p.Lys58Glu)

gnomAD frequency: 0.00007  dbSNP: rs201392711

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197397	SCV000251607	likely pathogenic	not provided	2014-05-19	criteria provided, single submitter	clinical testing	p.Lys58Glu (AAG>GAG): c.172 A>G in exon 2 of the HARS2 gene (NM_012208.2). The K58E missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid substitution is non-conservative in that a positively charged Lysine residue is replaced by a negatively charged Glutamic acid residue. This change occurs at a position that is highly conserved in the HARS2 protein and in silico analysis predict K58E is likely damaging to the structure/function of the protein. Therefore, K58E is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).
Invitae	RCV000197397	SCV002199503	likely pathogenic	not provided	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 58 of the HARS2 protein (p.Lys58Glu). This variant is present in population databases (rs201392711, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Perrault syndrome (PMID: 31449985). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214542). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HARS2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000782168	SCV000920636	likely pathogenic	Perrault syndrome 2	2019-05-20	no assertion criteria provided	clinical testing	Variant detected as compound heterozygous, together with c.448C>T in three siblings (two girls) with progressive sensorineural hearing impairment. Signs of premature ovarian failure were uncertain due to their young age.