Submissions for variant NM_006767.4(LZTR1):c.2407-2A>G

gnomAD frequency: 0.00001  dbSNP: rs1158550690

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000997883	SCV001153638	likely pathogenic	not provided	2017-01-01	criteria provided, single submitter	clinical testing
New York Genome Center	RCV001291825	SCV001480448	pathogenic	Noonan syndrome 2	2020-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001291825	SCV002051282	likely pathogenic	Noonan syndrome 2	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.2407-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249908 control chromosomes. c.2407-2A>G has been reported in the literature as a compound heterozygous genotype in three individuals from a single family affected with Autosomal recessive Noonan Syndrome (example, Johnston_2018). Of note, the obligate carrier parents in this family were nondysmorphic and had no cardiac anomalies. Additionally, the clinical features of Schwannomatosis in the obligate carrier father were not specified/reported in this study. It has also been reported as a VUS in settings of Schwannomatosis (example, Louvrier_2018 cited in Deng_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014). Based on the evidence outlined above, the variant was classified as likely pathogenic for NSRD and/or risk for multiple Schwannomas.
Invitae	RCV000997883	SCV002266949	pathogenic	not provided	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 20 of the LZTR1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with LZTR1-related conditions (PMID: 29469822, 35979676). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 809337). 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002454247	SCV002738573	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-02-09	criteria provided, single submitter	clinical testing	The c.2407-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 21 in the LZTR1 gene. This alteration occurs at the 3' terminus of the LZTR1 gene and is not expected to trigger nonsense-mediated mRNA decay. This variant has been reported in trans with another LZTR1 alteration (p.R697Q) in a child with features of Noonan syndrome and in the same couple's identical twin pregnancy affected with hydrops and congenital heart defects (Johnston JJ et al. Genet Med, 2018 10;20:1175-1185). This variant has also been identified in an individual with schwannomatosis (Louvrier C et al. Neuro Oncol, 2018 Jun;20:917-929). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000997883	SCV003845490	likely pathogenic	not provided	2023-03-02	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34308104, 29469822, 29409008)
Institute of Human Genetics, University of Leipzig Medical Center	RCV003227886	SCV003925636	likely pathogenic	Schwannomatosis 2	2023-12-04	criteria provided, single submitter	clinical testing	Criteria applied: PS4,PVS1_MOD,PM2_SUP
Baylor Genetics	RCV003227886	SCV004191840	pathogenic	Schwannomatosis 2	2022-03-10	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000997883	SCV001552432	uncertain significance	not provided		no assertion criteria provided	clinical testing	The LZTR1 c.2407-2A>G variant was identified in 1 of 24 proband chromosomes (frequency: 0.04167) from 12 families with Noonan synrome (Johnston_2018_PMID: 29469822). Johnston et al. studied 12 families with a total of 23 affected children with features of Noonan syndrome with variable expressivity; all had unaffected parents. All of the affected children harbored biallelic pathogenic mutations in LZTR1; the variant c.2407-2A>G was found in the compound heterozygote state with the variant p.R697Q in one child and her twin siblings who died midgestation. Their parents were each carriers for the c.2407-2A>G and p.R697Q variants and were unaffected. Other mutations included loss of function, missense, and canonical and non-canonical splicing variants (Johnston_2018_PMID: 29469822). The variant was also identified in dbSNP (ID: rs1158550690) and in the LOVD 3.0 database. The variant was not identified in the ClinVar, Clinvitae, COGR, Cosmic, MutDB, UMD-LSDB or ARUP Laboratories databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2407-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. Further, 4 out of 4 programs predict a loss of a 3' splice site at c.2407. The c.2407-2A nucleotide is conserved across mammals and other organisms and is predicted to be disease causing by MutationTaster. However, the predicted loss of splicing occurs in the last exon of this gene, therefore the effect on the protein is unknown. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. References: Johnston, Jennifer J., et al. "Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants." Genetics in Medicine (2018).