Submissions for variant NM_006767.4(LZTR1):c.1260+1G>A

gnomAD frequency: 0.00001  dbSNP: rs143868364

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001768491	SCV001992249	likely pathogenic	not provided	2022-07-06	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of exon 11 which contains the Kelch 6 domain and missense variants reported in the Human Gene Mutation Database in association with schwannomatosis (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001768491	SCV002114121	likely pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 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 (rs143868364, gnomAD 0.03%). 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: 1305284). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002425044	SCV002681947	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-11-15	criteria provided, single submitter	clinical testing	The c.1260+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 11 of the LZTR1 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is insufficient at this time (Ambry internal data). The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001768491	SCV003832290	likely pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004536285	SCV004103547	likely pathogenic	LZTR1-related disorder	2023-01-06	criteria provided, single submitter	clinical testing	The LZTR1 c.1260+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.033% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21347194-G-A). Variants that disrupt the consensus splice donor site in LZTR1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV003458230	SCV004177084	likely pathogenic	Noonan syndrome 10	2023-10-14	criteria provided, single submitter	clinical testing	The LZTR1 c.1260+1G>A variant was identified at a near heterozygous allelic fraction. This variant, to our knowledge, has not been reported in the medical literature. This variant has been reported in the ClinVar database as a likely pathogenic germline variant by three submitters and a germline variant of uncertain significance by one submitter (ClinVar ID: 1305284). This variant is only observed on 1/152,262 alleles in the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant occurs within the canonical splice donor site, which is predicted to disrupt RNA splicing. Based on the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the LZTR1 c.1260+1G>A variant is classified as likely pathogenic.
Baylor Genetics	RCV003464128	SCV004191199	likely pathogenic	Schwannomatosis 2	2023-10-25	criteria provided, single submitter	clinical testing