ClinVar Miner

Submissions for variant NM_002109.6(HARS1):c.1372G>A (p.Ala458Thr) (rs891844407)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000701574 SCV000830381 uncertain significance Usher syndrome, type 3B 2020-01-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 458 of the HARS protein (p.Ala458Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with HARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 578537). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825171 SCV000966443 likely benign not specified 2018-05-01 criteria provided, single submitter clinical testing p.Ala458Thr in exon 12 of HARS: This variant is classified as likely benign and it is not expected to have clinical significance due to a lack of conservation a cross species, including mammals. Of note, over ten mammals have a threonine at this position despite high nearby amino acid conservation. In addition, computat ional prediction tools do not suggest a high likelihood of impact to the protein . This variant has been identified in 1/33580 Latino chromosomes by the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs891844407 ). ACMG/AMP Criteria applied: PM2, BP4_Strong

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