Submissions for variant NM_001005373.4(LRSAM1):c.643C>A (p.Pro215Thr)

dbSNP: rs765389102

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000810293	SCV000477210	uncertain significance	Charcot-Marie-Tooth disease axonal type 2P	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000810293	SCV000950487	uncertain significance	Charcot-Marie-Tooth disease axonal type 2P	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 215 of the LRSAM1 protein (p.Pro215Thr). This variant is present in population databases (rs765389102, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LRSAM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 365016). 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 with a negative predictive value of 80%. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001090602	SCV001246227	uncertain significance	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002524585	SCV003557812	uncertain significance	Inborn genetic diseases	2022-10-11	criteria provided, single submitter	clinical testing	The c.643C>A (p.P215T) alteration is located in exon 10 (coding exon 9) of the LRSAM1 gene. This alteration results from a C to A substitution at nucleotide position 643, causing the proline (P) at amino acid position 215 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD), the c.643C>A alteration was observed in 0.002% (7/282,884) of total alleles studied. This amino acid position is conserved in available vertebrate species. The alteration is predicted deleterious by in silico models: The p.P215T alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genetics and Molecular Pathology, SA Pathology	RCV000810293	SCV004175286	uncertain significance	Charcot-Marie-Tooth disease axonal type 2P	2021-10-27	criteria provided, single submitter	clinical testing	The LRSAM1 c.643C>A variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE (PM2, PP3) This variant is a single nucleotide change from a cytosine to an adenine at position 643 which is predicted to change the proline at position 215 in the protein to threonine. The variant is in dbSNP (rs765389102) but is rare in population databases (gnomAD (v3.1.2) 3/152234, 0 homozygote) (PM2). The variant has been reported in ClinVar (ID#365016) as VUS, but is not presented in HGMD. Computational predictions support a deleterious effect on the gene or gene product (PP3).