Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Undiagnosed Diseases Network, |
RCV000625963 | SCV000746561 | pathogenic | Noonan syndrome 2 | 2017-05-01 | criteria provided, single submitter | clinical testing | This family has been reported in PMID:29469822. |
| Invitae | RCV002533148 | SCV003461978 | pathogenic | not provided | 2023-06-23 | criteria provided, single submitter | clinical testing | This variant is present in population databases (no rsID available, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects LZTR1 function (PMID: 30442762). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 522799). This premature translational stop signal has been observed in individual(s) with autosomal recessive Noonan syndrome (PMID: 29469822). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Tyr726*) 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). |
| Ambry Genetics | RCV003162767 | SCV003911696 | pathogenic | Hereditary cancer-predisposing syndrome; Cardiovascular phenotype | 2022-12-14 | criteria provided, single submitter | clinical testing | The p.Y726* pathogenic mutation (also known as c.2178C>A), located in coding exon 18 of the LZTR1 gene, results from a C to A substitution at nucleotide position 2178. This changes the amino acid from a tyrosine to a stop codon within coding exon 18. This mutation was confirmed in trans with another LZTR1 pathogenic mutation in siblings with Noonan syndrome phenotype (Johnston JJ et al. Genet Med, 2018 Oct;20:1175-1185) and has been identified in at least one individual with schwannoma(s) (Ambry internal data). 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. |