Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001228301 | SCV001400696 | pathogenic | not provided | 2022-06-08 | criteria provided, single submitter | clinical testing | 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: 955623). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln161Argfs*39) 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, 30442762, 30442766, 30481304, 30859559). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001290635 | SCV001478750 | uncertain significance | not specified | 2021-01-28 | criteria provided, single submitter | clinical testing | Variant summary: LZTR1 c.482delA (p.Gln161ArgfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251218 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.482delA in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014) or recessive type of Noonan Syndrome (Johnston_2018). Based on the evidence outlined above, the variant was classified as likely pathogenic for the risk of multiple schwannomas or recessive NS and as a variant of uncertain clinical significance for the phenotype dominant NSRD. |
| Ambry Genetics | RCV003163777 | SCV003911695 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-12-07 | criteria provided, single submitter | clinical testing | The c.482delA variant, located in coding exon 5 of the LZTR1 gene, results from a deletion of one nucleotide at nucleotide position 482, causing a translational frameshift with a predicted alternate stop codon (p.Q161Rfs*39). 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 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. |