Submissions for variant NM_006767.4(LZTR1):c.774del (p.Phe258fs)

dbSNP: rs780267761

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414560	SCV000491465	likely pathogenic	not provided	2023-05-21	criteria provided, single submitter	clinical testing	Observed in an individual with autism (Guo et al., 2019); 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; This variant is associated with the following publications: (PMID: 30504930, 30368668, 30481304, 25795793, 29469822, 30442766, 30859559, 24362817, 30442762, 25335493, 25480913)
Invitae	RCV000414560	SCV001404178	pathogenic	not provided	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe258Leufs*93) 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 (rs780267761, gnomAD 0.006%). 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: 372924). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002411278	SCV002669981	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-08-11	criteria provided, single submitter	clinical testing	The c.774delT pathogenic mutation, located in coding exon 8 of the LZTR1 gene, results from a deletion of one nucleotide at nucleotide position 774, causing a translational frameshift with a predicted alternate stop codon (p.F258Lfs*93). 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.
PreventionGenetics, part of Exact Sciences	RCV004530514	SCV004118811	likely pathogenic	LZTR1-related disorder	2023-08-10	criteria provided, single submitter	clinical testing	The LZTR1 c.774delT variant is predicted to result in a frameshift and premature protein termination (p.Phe258Leufs*93). To our knowledge, this variant has not been reported in an individual LZTR1-related disease. This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21344794-GT-G). Frameshift variants in LZTR1 are expected to be pathogenic for autosomal recessive Noonan syndrome and autosomal dominant susceptibility to schwannomatosis. However, the role of frameshift variants in autosomal dominant Noonan syndrome is uncertain (see below). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003476002	SCV004193612	likely pathogenic	Schwannomatosis 2	2023-07-23	criteria provided, single submitter	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291506	SCV001480011	association	Autism spectrum disorder		no assertion criteria provided	research