ClinVar Miner

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

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Total submissions: 3
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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 uncertain significance not provided 2023-01-16 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; Alters the last nucleotide of the exon and is predicted to damage/destroy the splice donor site but the effect on protein function is unclear
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.

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