Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV003216358 | SCV003911671 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-01-03 | criteria provided, single submitter | clinical testing | The p.Y691* pathogenic mutation (also known as c.2073C>G), located in coding exon 18 of the LZTR1 gene, results from a C to G substitution at nucleotide position 2073. This changes the amino acid from a tyrosine to a stop codon within coding exon 18. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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 pathogenic/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. |
| Baylor Genetics | RCV003466040 | SCV004191838 | likely pathogenic | LZTR1-related schwannomatosis | 2022-05-16 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV003549022 | SCV004270309 | pathogenic | not provided | 2025-01-21 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Tyr691*) in the LZTR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LZTR1 are known to be pathogenic (PMID: 24362817, 25335493, 25480913, 25795793, 29469822, 30368668, 30442762, 30442766, 30481304, 30859559). 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: 2496781). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. |