Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Victorian Clinical Genetics Services, |
RCV002273086 | SCV002557684 | uncertain significance | Noonan syndrome 10 | 2022-06-24 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with Noonan syndrome 10 (MIM#616564). Missense variants in this gene enhance stimulus-dependent RAS-MAPK signaling, consistent with lost LZTR1 function as a negative regulator of this pathway (PMID: 30481304). Susceptibility to schwannomatosis-2 (MIM#615670) requires a somatic second hit and is the result of a loss of function mechanism (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0213 - In-frame duplication in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated BTB/POZ domain (DECIPHER). (I) 0705 - No comparable insertion or duplication variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
Ambry Genetics | RCV002409629 | SCV002715858 | uncertain significance | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-05-24 | criteria provided, single submitter | clinical testing | The c.1685_1702dup18 variant (also known as p.L562_R567dup), located in coding exon 15 of the LZTR1 gene, results from an in-frame duplication of 18 nucleotides at nucleotide positions 1685 to 1702. This results in the duplication of 6 extra residues (LEQLCR) between codons 562 and 567. This amino acid region is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
St. |
RCV002273086 | SCV003842988 | uncertain significance | Noonan syndrome 10 | 2023-01-10 | criteria provided, single submitter | clinical testing | The LZTR1 c.1685_1702dup (p.Leu562_Arg567dup) change inserts eighteen nucleotides at position 1685-1702, resulting in an in-frame duplication of 6 amino acid residues. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Algorithms that predict the impact of sequence changes on splicing indicate that this variant does not affect splicing. To our knowledge, in-frame duplications in the LZTR1 gene have not been reported in individuals with Noonan syndrome or Schwannomatosis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
Labcorp Genetics |
RCV003565509 | SCV004320195 | uncertain significance | not provided | 2024-01-30 | criteria provided, single submitter | clinical testing | This variant, c.1685_1702dup, results in the insertion of 6 amino acid(s) of the LZTR1 protein (p.Leu562_Arg567dup), but otherwise preserves the integrity of the reading frame. 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: 1699229). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. |