ClinVar Miner

Submissions for variant NM_138361.5(LRSAM1):c.569G>A (p.Arg190Gln) (rs142782210)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218598 SCV000279948 uncertain significance not specified 2017-06-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LRSAM1 gene. The c.569 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.569 G>A variant is observed in 18/48698 (0.04%) alleles from individuals of European background, including one individual who was homozygous for the variant (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.569 G>A creates a cryptic acceptor site downstream of the natural acceptor site in intron 8 which may supplant the natural acceptor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown. If the c.569 G>A variant does not effect splicing, it will result in a R190Q missense variant. The R190Q variant is a a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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.
Illumina Clinical Services Laboratory,Illumina RCV000362333 SCV000477208 uncertain significance Charcot-Marie-Tooth disease, type 2 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000702205 SCV000831049 uncertain significance Charcot-Marie-Tooth disease type 2P 2018-02-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 190 of the LRSAM1 protein (p.Arg190Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs142782210, ExAC 0.04%), 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: 234876). 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 glutamine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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