ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.2347dup (p.Thr783fs)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002635296 SCV002966454 pathogenic not provided 2022-06-14 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the LZTR1 protein in which other variant(s) (p.Leu806Trp) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with LZTR1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the LZTR1 gene (p.Thr783Asnfs*68). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acid(s) of the LZTR1 protein and extend the protein by 9 additional amino acid residues.
Ambry Genetics RCV003167523 SCV003861190 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-12-02 criteria provided, single submitter clinical testing The c.2347dupA variant, located in coding exon 20 of the LZTR1 gene, results from a duplication of A at nucleotide position 2347, causing a translational frameshift with a predicted alternate stop codon (p.T783Nfs*68). This alteration occurs at the 3' terminus of the LZTR1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 9 amino acids. This frameshift impacts the last 58 AAamino acids of the native protein. However, frameshifts are typically deleterious in nature. 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, the association of this alteration with LZTR1-related schwannomatosis (SWN) and autosomal recessive Noonan syndrome is unknown; however, the association of this alteration with autosomal dominant Noonan syndrome is unlikely.
GeneDx RCV002635296 SCV004036329 likely pathogenic not provided 2023-03-23 criteria provided, single submitter clinical testing Frameshift variant in which the last 58 amino acids are replaced with 67 different amino acids; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge

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