ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.509G>T (p.Arg170Leu)

dbSNP: rs781431741
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001878863 SCV002131765 uncertain significance not provided 2021-03-27 criteria provided, single submitter clinical testing 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. This variant disrupts the c.509G nucleotide in the LZTR1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 25480913, 30481304, 30732632). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with schwannomatosis (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 170 of the LZTR1 protein (p.Arg170Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon.
Ambry Genetics RCV002334774 SCV002641930 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-06-23 criteria provided, single submitter clinical testing The c.509G>T variant (also known as p.R170L), located in coding exon 5 of the LZTR1 gene, results from a G to T substitution at nucleotide position 509. The amino acid change results in arginine to leucine at codon 170, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 5, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site, and RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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, c.509G>T is likely pathogenic for an increased risk of nerve sheath tumors 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.
Revvity Omics, Revvity RCV001878863 SCV003815331 uncertain significance not provided 2023-05-15 criteria provided, single submitter clinical testing

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