Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002434696 | SCV002678544 | likely pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-08-10 | criteria provided, single submitter | clinical testing | The c.1260G>A variant (also known as p.Q420Q), located in coding exon 11 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1260. This nucleotide substitution does not change the glutamine at codon 420. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This alteration has been observed in at least one individual with a personal history consistent with schwannomaatosis (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 may result in the creation or strengthening of a novel splice donor site. Loss-of-function variants in LZTR1 are related to an increased risk for schwannomas and autosomal recessive Noonan syndrome; however, such associations with autosomal dominant Noonan syndrome have not been observed (Piotrowski A et al. Nat Genet. 2014 Feb;46:182-7; Yamamoto GL et al. J Med Genet. 2015 Jun;52:413-21; Johnston JJ et al. Genet Med. 2018 10;20:1175-1185). Based on the supporting evidence, this variant is likely 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; however, the association of this alteration with autosomal dominant Noonan syndrome is unlikely. |
| Labcorp Genetics |
RCV003099916 | SCV003514060 | uncertain significance | not provided | 2023-07-15 | criteria provided, single submitter | clinical testing | This sequence change affects codon 420 of the LZTR1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LZTR1 protein. This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.008%). 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: 1763028). 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 | RCV003471362 | SCV004193694 | uncertain significance | Schwannomatosis 2 | 2022-12-05 | criteria provided, single submitter | clinical testing |