Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000190742 | SCV000244183 | uncertain significance | Inborn genetic diseases | 2019-11-14 | criteria provided, single submitter | clinical testing | The p.P707L variant (also known as c.2120C>T), located in coding exon 24 of the LRSAM1 gene, results from a C to T substitution at nucleotide position 2120. The proline at codon 707 is replaced by leucine, an amino acid with similar properties. This variant has been reported in one patient with axonal neuropathy affecting both sensory and motor nerves and has been shown to result in an impaired function of the mutant protein (Hakonen JE et al. Hum. Mol. Genet., 2017 06;26:2034-2041). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Molecular Genetics Laboratory, |
RCV001173632 | SCV001336734 | likely pathogenic | Charcot-Marie-Tooth disease | criteria provided, single submitter | clinical testing | ||
| Invitae | RCV001224770 | SCV001396990 | pathogenic | Charcot-Marie-Tooth disease axonal type 2P | 2023-01-03 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro707 amino acid residue in LRSAM1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects LRSAM1 function (PMID: 28335037). 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 expected to disrupt LRSAM1 protein function. ClinVar contains an entry for this variant (Variation ID: 208726). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 28335037, 32376792; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 707 of the LRSAM1 protein (p.Pro707Leu). |
| Institute of Human Genetics, |
RCV001224770 | SCV001428627 | likely pathogenic | Charcot-Marie-Tooth disease axonal type 2P | 2017-05-15 | criteria provided, single submitter | clinical testing |