ClinVar Miner

Submissions for variant NM_138361.5(LRSAM1):c.1939G>A (p.Val647Ile) (rs879254326)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000237094 SCV000294191 uncertain significance not provided 2016-05-27 criteria provided, single submitter clinical testing The V647I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant 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. The V647I 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 that is not conserved, and 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 variant or a rare benign variant.
Invitae RCV000706947 SCV000836022 uncertain significance Charcot-Marie-Tooth disease type 2P 2018-01-16 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 647 of the LRSAM1 protein (p.Val647Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LRSAM1-related disease. ClinVar contains an entry for this variant (Variation ID: 246595). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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