Submissions for variant NM_006767.4(LZTR1):c.1449G>A (p.Gln483=)

gnomAD frequency: 0.00001  dbSNP: rs1203145822

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002394517	SCV002698082	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-02-29	criteria provided, single submitter	clinical testing	The c.1449G>A variant (also known as p.Q483Q), located in coding exon 13 of the LZTR1 gene. This variant results from a G to A substitution at nucleotide position 1449. This nucleotide substitution does not change the glutamine at codon 483. However, this change occurs in the last base pair of coding exon 13, 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 will 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, this alteration has been observed in at least one individual with a personal history that is consistent with LZTR1-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 likely 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.
GeneDx	RCV003314733	SCV004014480	likely pathogenic	not provided	2024-01-11	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 supports a deleterious effect on splicing
PreventionGenetics, part of Exact Sciences	RCV004534081	SCV004119315	uncertain significance	LZTR1-related disorder	2023-04-07	criteria provided, single submitter	clinical testing	The LZTR1 c.1449G>A variant is not predicted to result in an amino acid change (p.=). This variant is located at the last nucleotide of exon 13 and is predicted to impact splicing (Alamut Visual Plus v1.6.1). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is listed in ClinVar as likely pathogenic based in part on another laboratory's internal data (https://preview.ncbi.nlm.nih.gov/clinvar/variation/1772861/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003314733	SCV005813123	uncertain significance	not provided	2024-08-28	criteria provided, single submitter	clinical testing	This sequence change affects codon 483 of the LZTR1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LZTR1 protein. This variant also falls at the last nucleotide of exon 13, which is part of the consensus splice site for this exon. 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: 1772861). 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.