Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003739813 | SCV004558078 | pathogenic | not provided | 2023-08-16 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln441*) 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). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004587554 | SCV005075807 | pathogenic | Noonan syndrome 2 | 2024-04-29 | criteria provided, single submitter | clinical testing | Variant summary: LZTR1 c.1321C>T (p.Gln441X) 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. The variant was absent in 249452 control chromosomes. To our knowledge, no occurrence of c.1321C>T in individuals affected with Noonan Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2899790). Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014) and recessive Noonan syndrome (Johnston_2018). Based on the evidence outlined above, the variant was classified as pathogenic for the risk of multiple schwannomas and recessive Noonan syndrome and as a variant of uncertain clinical significance for dominant Noonan syndrome. |
| Ambry Genetics | RCV004992774 | SCV005616200 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2024-11-08 | criteria provided, single submitter | clinical testing | The p.Q441* pathogenic mutation (also known as c.1321C>T), located in coding exon 12 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1321. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This variant has been observed in at least one individual with a personal and/or family history that is consistent with LZTR1-related schwannomatosis (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD).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. |