Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001921046 | SCV002197147 | uncertain significance | not provided | 2024-11-11 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 802 of the LZTR1 protein (p.Lys802Asn). This variant also falls at the last nucleotide of exon 20, 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: 1415669). 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 disruptive. 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. |
| Ambry Genetics | RCV004558732 | SCV005047874 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-08-29 | criteria provided, single submitter | clinical testing | The c.2406G>C pathogenic mutation (also known as p.K802N), located in coding exon 20 of the LZTR1 gene, results from a G to C substitution at nucleotide position 2406. The amino acid change results in lysine to asparagine at codon 802, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 20, which makes it likely to have some effect on normal mRNA splicing. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with LZTR1-related disease (Ambry internal data).This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this variant is pathogenic for an increased risk of LZTR1-related schwannomatosis (SWN) and would be expected to cause autosomal recessive Noonan syndrome when present along with a second pathogenic or likely pathogenic variant on the other allele. |