Submissions for variant NM_001005373.4(LRSAM1):c.1589G>A (p.Arg530Gln)

gnomAD frequency: 0.00001  dbSNP: rs760321710

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427596	SCV000535373	uncertain significance	not provided	2016-12-29	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the LRSAM1 gene. The R530Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R530Q 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 R530Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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	RCV001068726	SCV001233855	uncertain significance	Charcot-Marie-Tooth disease axonal type 2P	2023-02-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 530 of the LRSAM1 protein (p.Arg530Gln). This variant is present in population databases (rs760321710, gnomAD 0.007%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 34190362). ClinVar contains an entry for this variant (Variation ID: 392156). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRSAM1 protein function. This variant disrupts the p.Arg530 amino acid residue in LRSAM1. Other variant(s) that disrupt this residue have been observed in individuals with LRSAM1-related conditions (PMID: 34190362, 35234685), which suggests that this may be a clinically significant amino acid residue. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000427596	SCV004225099	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing	BP4