NM_001005373.4:c.1780C>T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001005373.4(LRSAM1):c.1780C>T(p.Arg594Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,612,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001005373.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRSAM1 | NM_001005373.4 | c.1780C>T | p.Arg594Cys | missense_variant | Exon 23 of 26 | ENST00000300417.11 | NP_001005373.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000221 AC: 55AN: 249378Hom.: 0 AF XY: 0.000244 AC XY: 33AN XY: 135054
GnomAD4 exome AF: 0.000191 AC: 279AN: 1460100Hom.: 0 Cov.: 32 AF XY: 0.000172 AC XY: 125AN XY: 726416
GnomAD4 genome AF: 0.000184 AC: 28AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:2
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. -
LRSAM1: PM2 -
Inborn genetic diseases Uncertain:1
The p.R594C variant (also known as c.1780C>T), located in coding exon 21 of the LRSAM1 gene, results from a C to T substitution at nucleotide position 1780. The arginine at codon 594 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant Charcot-Marie-Tooth disease, type 2P; however, its contribution to the development of autosomal recessive Charcot-Marie-Tooth disease, type 2P is uncertain. -
LRSAM1-related disorder Uncertain:1
The LRSAM1 c.1780C>T variant is predicted to result in the amino acid substitution p.Arg594Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.067% of alleles in individuals of European (Finnish) descent in gnomAD. Alternative variant at the same codon p.Arg595His has been observed in an individual with Charcot-Marie-Tooth disease (Table S2, Volodarsky et al 2021. PubMed ID: 32376792). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Charcot-Marie-Tooth disease axonal type 2P Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 594 of the LRSAM1 protein (p.Arg594Cys). This variant is present in population databases (rs150062009, gnomAD 0.06%). 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: 423366). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LRSAM1 protein function with a positive 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at