Submissions for variant NM_006767.4(LZTR1):c.955del (p.Gln319fs)

dbSNP: rs1386054181

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Medicine Lab, University of California San Francisco	RCV001007902	SCV001167608	uncertain significance	Congenital diaphragmatic hernia	2018-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860580	SCV002132954	pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln319Argfs*32) 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 present in population databases (no rsID available, gnomAD 0.003%). 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: 816896). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001860580	SCV002526507	likely pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD)
Ambry Genetics	RCV002372731	SCV002690763	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2025-01-27	criteria provided, single submitter	clinical testing	The c.955delC variant, located in coding exon 9 of the LZTR1 gene, results from a deletion of one nucleotide at nucleotide position 955, causing a translational frameshift with a predicted alternate stop codon (p.Q319Rfs*32). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587012	SCV005075913	pathogenic	Noonan syndrome 2	2024-04-01	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.955delC (p.Gln319ArgfsX32) 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 1.3e-05 in 157692 control chromosomes (gnomAD v2.1). To our knowledge, no occurrence of c.955delC in individuals affected with Noonan Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 816896). 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 pathogenic for the risk of multiple schwannomas and recessive Noonan syndrome and as a variant of uncertain clinical significance for dominant Noonan syndrome.