ClinVar Miner

Submissions for variant NM_015340.4(LARS2):c.1947C>A (p.Asp649Glu)

gnomAD frequency: 0.00022  dbSNP: rs143155251
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000616471 SCV000711538 likely benign not specified 2016-06-28 criteria provided, single submitter clinical testing p.Asp649Glu in exon 17 of LARS2: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, >5 mammals have a glutamic acid (Glu) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not sug gest a high likelihood of impact to the protein. This variant has been identifie d in 4/66738 European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs143155251).
GeneDx RCV001595024 SCV001829305 uncertain significance not provided 2020-12-11 criteria provided, single submitter clinical testing Observed in a patient with suspected mitochondrial disease in published literature (Nogueira et al., 2019); however, this patient did not have hearing loss; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30831263)
Invitae RCV001595024 SCV002210456 uncertain significance not provided 2022-08-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 649 of the LARS2 protein (p.Asp649Glu). This variant is present in population databases (rs143155251, gnomAD 0.05%). This missense change has been observed in individual(s) with mitochondrial disease (PMID: 30831263). ClinVar contains an entry for this variant (Variation ID: 504797). 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 glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV002529289 SCV003740246 uncertain significance Inborn genetic diseases 2022-05-13 criteria provided, single submitter clinical testing The c.1947C>A (p.D649E) alteration is located in exon 17 (coding exon 15) of the LARS2 gene. This alteration results from a C to A substitution at nucleotide position 1947, causing the aspartic acid (D) at amino acid position 649 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity RCV001595024 SCV003816482 uncertain significance not provided 2021-03-12 criteria provided, single submitter clinical testing

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