ClinVar Miner

Submissions for variant NM_138361.5(LRSAM1):c.1780C>T (p.Arg594Cys) (rs150062009)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478781 SCV000573055 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LRSAM1 gene. The R594C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R594C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R594C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in Human Gene Mutation Database in association with LRSAM1-related disorders (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 RCV000690760 SCV000818486 uncertain significance Charcot-Marie-Tooth disease type 2P 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 594 of the LRSAM1 protein (p.Arg594Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs150062009, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with LRSAM1-related disease. ClinVar contains an entry for this variant (Variation ID: 423366). 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 disruptive, 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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