ClinVar Miner

Submissions for variant NM_002109.6(HARS1):c.1217C>A (p.Thr406Asn)

gnomAD frequency: 0.00003  dbSNP: rs369070016
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000650152 SCV000771989 uncertain significance Usher syndrome type 3B 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 406 of the HARS protein (p.Thr406Asn). This variant is present in population databases (rs369070016, gnomAD 0.004%). 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: 540205). 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%. 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.
Mayo Clinic Laboratories, Mayo Clinic RCV001508174 SCV001714147 uncertain significance not provided 2021-11-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001508174 SCV002050032 uncertain significance not provided 2020-11-10 criteria provided, single submitter clinical testing The HARS1 (AKA: HARS) c.1217C>A; p.Thr406Asn variant (rs369070016), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 540205). This variant is found in the general population with an overall allele frequency of 0.0004% (1/275,000 alleles) in the Genome Aggregation Database. The threonine at codon 406 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.248). Based on the available information, the clinical significance of this variant is uncertain.
Ambry Genetics RCV002461963 SCV002755245 uncertain significance Inborn genetic diseases 2020-06-23 criteria provided, single submitter clinical testing The p.T406N variant (also known as c.1217C>A), located in coding exon 11 of the HARS gene, results from a C to A substitution at nucleotide position 1217. The threonine at codon 406 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV001508174 SCV004235254 uncertain significance not provided 2023-05-19 criteria provided, single submitter clinical testing

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