Submissions for variant NM_006767.4(LZTR1):c.1602del (p.Lys534fs)

dbSNP: rs1268674934

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001972352	SCV002238173	pathogenic	not provided	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys534Asnfs*22) in the LZTR1 gene. It is expected to result in an absent or disrupted protein product. 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with schwannomatosis (PMID: 28365909). ClinVar contains an entry for this variant (Variation ID: 1456304). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002398011	SCV002706388	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-01-04	criteria provided, single submitter	clinical testing	The c.1602delA pathogenic mutation, located in coding exon 14 of the LZTR1 gene, results from a deletion of one nucleotide at nucleotide position 1602, causing a translational frameshift with a predicted alternate stop codon (p.K534Nfs*22). This mutation has been reported in multiple individuals with schwannomatosis (Paganini I et al. Eur J Hum Genet, 2015 Jul;23:963-8; Caltabiano R et al. Childs Nerv Syst, 2017 Jun;33:933-940). 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 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.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001972352	SCV005198705	pathogenic	not provided	2023-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238114	SCV005886527	pathogenic	Noonan syndrome 2	2025-02-13	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1602delA (p.Lys534AsnfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.3e-07 in 1598494 control chromosomes (gnomAD v4.1). c.1602delA has been reported in the literature in the heterozygous state in individuals affected with Schwannomatosis or Noonan Syndrome (e.g. Paganini_2015, Uliana_2024). The following publications have been ascertained in the context of this evaluation (PMID: 25335493, 39062695). ClinVar contains an entry for this variant (Variation ID: 1456304). Germline loss of function mutations in LZTR1 have been associated with either an inherited autosomal dominant disorder of multiple schwannomas (Piotrowski_2014), autosomal recessive or autosomal dominant Noonan syndrome. Based on the evidence outlined above, the variant was classified as pathogenic.