ClinVar Miner

Submissions for variant NM_002109.6(HARS1):c.1393A>C (p.Ile465Leu)

dbSNP: rs754304255
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris RCV001007622 SCV001142643 pathogenic Cerebellar ataxia; Motor delay; Scoliosis; Dysarthria; Pes planus; Urinary urgency; Microcephaly; Intellectual disability; Joint laxity; Hammertoe; Distal muscle weakness 2019-01-01 criteria provided, single submitter research
Invitae RCV001246783 SCV001420165 uncertain significance Usher syndrome type 3B 2024-01-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 465 of the HARS protein (p.Ile465Leu). This variant is present in population databases (rs754304255, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Usher syndrome and/or multi-system ataxic syndrome (PMID: 32333447; Invitae). ClinVar contains an entry for this variant (Variation ID: 804288). 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 not expected to disrupt HARS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect HARS function (PMID: 32333447). 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.
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris RCV001644878 SCV001519138 pathogenic Spastic ataxia 2021-01-04 criteria provided, single submitter research
Kariminejad - Najmabadi Pathology & Genetics Center RCV001814247 SCV001755342 likely pathogenic Peripheral neuropathy 2021-07-10 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003973002 SCV004790779 uncertain significance HARS1-related condition 2024-02-08 criteria provided, single submitter clinical testing The HARS1 c.1393A>C variant is predicted to result in the amino acid substitution p.Ile465Leu. This variant was reported in the compound heterozygous state along with a second potentially causative variant in two sisters with multisystem ataxic syndrome (Galatolo et al. 2020. PubMed ID: 32333447; Galatolo et al. 2021. PubMed ID: 34445196). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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