Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001290561 | SCV001478635 | uncertain significance | not specified | 2021-01-21 | criteria provided, single submitter | clinical testing | Variant summary: LZTR1 c.658C>T (p.Gln220X) 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. The variant allele was found at a frequency of 8e-06 in 251286 control chromosomes (gnomAD). 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.658C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014). Based on the evidence outlined above, the variant was classified as likely pathogenic for the risk of multiple schwannomas and as a variant of uncertain clinical significance for the phenotype NSRD. |
| Ambry Genetics | RCV002375333 | SCV002667164 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2024-01-26 | criteria provided, single submitter | clinical testing | The p.Q220* pathogenic mutation (also known as c.658C>T), located in coding exon 8 of the LZTR1 gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from a glutamine to a stop codon within coding exon 8. 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). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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. |
| Invitae | RCV002543010 | SCV003450091 | pathogenic | not provided | 2023-08-22 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 996239). This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. This variant is present in population databases (rs749437251, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Gln220*) 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). |
| Baylor Genetics | RCV003469506 | SCV004193626 | likely pathogenic | Schwannomatosis 2 | 2023-06-30 | criteria provided, single submitter | clinical testing |