Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002460324 | SCV002618100 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2023-09-05 | criteria provided, single submitter | clinical testing | The c.1149G>C pathogenic mutation (also known as p.E383D), located in coding exon 10 of the LZTR1 gene, results from a G to C substitution at nucleotide position 1149. The glutamic acid at codon 383 is replaced by aspartic acid, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 10, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. 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. |
| Baylor Genetics | RCV003464453 | SCV004193608 | uncertain significance | Schwannomatosis 2 | 2023-07-25 | criteria provided, single submitter | clinical testing |