Submissions for variant NM_006767.4(LZTR1):c.320G>C (p.Arg107Thr)

gnomAD frequency: 0.00001  dbSNP: rs1301901369

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002449402	SCV002611869	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-23	criteria provided, single submitter	clinical testing	The c.320G>C variant (also known as p.R107T), located in coding exon 3 of the LZTR1 gene, results from a G to C substitution at nucleotide position 320. The amino acid change results in arginine to threonine at codon 107, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 3, 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 RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001723275	SCV004530161	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 107 of the LZTR1 protein (p.Arg107Thr). This variant also falls at the last nucleotide of exon 3, 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: 1297494). 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 disruptive. 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.
Baylor Genetics	RCV004571070	SCV005060628	uncertain significance	Schwannomatosis 2	2024-02-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001723275	SCV005376741	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site but the effect on protein function is unclear; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723275	SCV001956910	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723275	SCV001966403	uncertain significance	not provided		no assertion criteria provided	clinical testing