Submissions for variant NM_006767.4(LZTR1):c.1615G>A (p.Gly539Ser)

gnomAD frequency: 0.00001  dbSNP: rs1232362523

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293512	SCV001482101	uncertain significance	not specified	2021-02-22	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1615G>A (p.Gly539Ser) results in a non-conservative amino acid change located in the BTB/POZ domain of the encoded protein sequence. The variant impacts the last nucleotide in exon 14. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 230344 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1615G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001863176	SCV002133515	uncertain significance	not provided	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 539 of the LZTR1 protein (p.Gly539Ser). This variant also falls at the last nucleotide of exon 14, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 997883). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002402813	SCV002705795	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-06-24	criteria provided, single submitter	clinical testing	The p.G539S variant (also known as c.1615G>A), located in coding exon 14 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1615. The glycine at codon 539 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 14, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. 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; however, direct evidence is insufficient at this time (Ambry internal data). In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004528451	SCV004110349	uncertain significance	LZTR1-related disorder	2023-09-13	criteria provided, single submitter	clinical testing	The LZTR1 c.1615G>A variant is predicted to result in the amino acid substitution p.Gly539Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21348558-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003469511	SCV004191303	uncertain significance	Schwannomatosis 2	2023-08-05	criteria provided, single submitter	clinical testing