Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000681273 | SCV000808735 | likely pathogenic | not provided | 2024-02-01 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27535533) |
| Labcorp Genetics |
RCV000681273 | SCV002312408 | uncertain significance | not provided | 2024-01-11 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 10 of the LZTR1 gene. It does not directly change the encoded amino acid sequence of the LZTR1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs542715642, gnomAD 0.006%). 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: 561842). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Ambry Genetics | RCV002458194 | SCV002617423 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-09-05 | criteria provided, single submitter | clinical testing | The c.1149+3A>G pathogenic mutation results from an A to G substitution 3 nucleotides after coding exon 10 in the LZTR1 gene. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with LZTR1-related disease (Ambry internal data). In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, other alterations impacting the same splice donor site (c.1149+1G>A and c.1149+1G>T) have a similar impact on splicing and have been confirmed in trans or detected in the compound heterozygous state with pathogenic LZTR1 alterations in patients with features consistent with Noonan syndrome (Ambry internal data; Johnston JJ et al. Genet Med, 2018 10;20:1175-1185; Pagnamenta AT et al. Clin Genet, 2019 06;95:693-703; Perin F et al. Rev Esp Cardiol (Engl Ed), 2019 Nov;72:978-980). 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155282 | SCV003844509 | uncertain significance | not specified | 2023-02-10 | criteria provided, single submitter | clinical testing |