Submissions for variant NM_006767.4(LZTR1):c.320+1G>A

dbSNP: rs943939913

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699489	SCV002103817	likely pathogenic	Schwannomatosis	2024-07-19	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.320+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. 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 4e-06 in 251202 control chromosomes. To our knowledge, no occurrence of c.320+1G>A in individuals affected with LZTR1-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1343619). 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.
Ambry Genetics	RCV002324215	SCV002609153	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-07-07	criteria provided, single submitter	clinical testing	The c.320+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 3 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; however, direct evidence is insufficient at this time (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this variant is likely pathogenic for an increased risk of nerve sheath tumors 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	RCV002543322	SCV003444139	likely pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 3 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 has not been reported in the literature in individuals affected with LZTR1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 1343619). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Baylor Genetics	RCV003470941	SCV004191194	likely pathogenic	LZTR1-related schwannomatosis	2023-10-27	criteria provided, single submitter	clinical testing