ClinVar Miner

Submissions for variant NM_138361.5(LRSAM1):c.184G>A (p.Val62Ile) (rs570688892)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235341 SCV000292926 uncertain significance not provided 2015-06-10 criteria provided, single submitter clinical testing The V62I variant has not been published as pathogenic, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. V62I was not observed with any significant frequency in the 1000 Genomes Database. The V62I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species, and Isoleucine is observed at this position in evolution. In silico analysis predicts this variant likely does not alter the protein structure/function. Additionally, missense variants in the LRSAM1 gene have not been reported in association with neuropathy (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic or a rare benign variant.
Invitae RCV000649904 SCV000771740 uncertain significance Charcot-Marie-Tooth disease type 2P 2017-10-12 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 62 of the LRSAM1 protein (p.Val62Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs570688892, ExAC 0.009%). This variant has not been reported in the literature in individuals with LRSAM1-related disease. ClinVar contains an entry for this variant (Variation ID: 245795). 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 isoleucine 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.

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