Submissions for variant NM_006767.4(LZTR1):c.1785+1G>A

gnomAD frequency: 0.00001  dbSNP: rs145594158

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658061	SCV000779832	pathogenic	not provided	2024-08-15	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36307859, 37936555)
Baylor Genetics	RCV001788313	SCV002030248	likely pathogenic	LZTR1-related schwannomatosis	2021-02-09	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mendelics	RCV002248854	SCV002517584	pathogenic	Noonan syndrome 2	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002406499	SCV002714969	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-12-21	criteria provided, single submitter	clinical testing	The c.1785+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 15 of the LZTR1 gene. This nucleotide 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, 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, 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; however, the association of this alteration with autosomal dominant Noonan syndrome is unlikely.
Genetics and Molecular Pathology, SA Pathology	RCV001788313	SCV002761744	pathogenic	LZTR1-related schwannomatosis	2022-07-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001788313	SCV004191193	pathogenic	LZTR1-related schwannomatosis	2024-02-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000658061	SCV004410447	pathogenic	not provided	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 15 of the LZTR1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LZTR1 are known to be pathogenic (PMID: 24362817, 25335493, 25480913, 25795793, 29469822, 30368668, 30442762, 30442766, 30481304, 30859559). This variant is present in population databases (rs145594158, gnomAD 0.005%). Disruption of this splice site has been observed in individual(s) with LTZR1-related conditions and/or schwannomatosis (PMID: 25480913, 36307859). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 546216). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002248854	SCV005381174	likely pathogenic	Noonan syndrome 2	2024-08-30	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1785+1G>A 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of LZTR1 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-06 in 248126 control chromosomes (gnomAD). c.1785+1G>A has been reported in the literature in at least one compound heterozygous prenatal case with cystic hygroma, hydrops fetalis, and a hypoplastic left heart (e.g., Fu_2022); the variant was identified through whole-exome sequencing and confirmed to be in trans with a second LZTR1 splice-site variant. To our knowledge, this variant has not been observed in patients with autosomal dominant Noonan syndrome or Schwannomatosis, and no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36307859, 24362817, 37936555). ClinVar contains an entry for this variant (Variation ID: 546216). Germline loss-of-function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014) and recessive Noonan syndrome (Johnston_2018). Based on the evidence outlined above, the variant was classified as likely pathogenic for the risk of multiple schwannomas and recessive Noonan syndrome.