Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002740685 | SCV003017230 | uncertain significance | not provided | 2023-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 451 of the LZTR1 protein (p.Glu451Asp). This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1971374). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Baylor Genetics | RCV003465823 | SCV004193666 | uncertain significance | Schwannomatosis 2 | 2023-05-11 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004559964 | SCV005047272 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-12-15 | criteria provided, single submitter | clinical testing | The c.1353G>C variant (also known as p.E451D), located in coding exon 12 of the LZTR1 gene, results from a G to C substitution at nucleotide position 1353. The amino acid change results in glutamic acid to aspartic acid at codon 451, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 31 amino acids; however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |