Submissions for variant NM_006767.4(LZTR1):c.2178C>A (p.Tyr726Ter)

dbSNP: rs1034395178

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000625963	SCV000746561	pathogenic	Noonan syndrome 2	2017-05-01	criteria provided, single submitter	clinical testing	This family has been reported in PMID:29469822.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002533148	SCV003461978	pathogenic	not provided	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr726*) 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 premature translational stop signal has been observed in individual(s) with autosomal recessive Noonan syndrome (PMID: 29469822). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 522799). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects LZTR1 function (PMID: 30442762). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003162767	SCV003911696	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-12-14	criteria provided, single submitter	clinical testing	The p.Y726* pathogenic mutation (also known as c.2178C>A), located in coding exon 18 of the LZTR1 gene, results from a C to A substitution at nucleotide position 2178. This changes the amino acid from a tyrosine to a stop codon within coding exon 18. This mutation was confirmed in trans with another LZTR1 pathogenic mutation in siblings with Noonan syndrome phenotype (Johnston JJ et al. Genet Med, 2018 Oct;20:1175-1185) and has been identified in at least one individual with schwannoma(s) (Ambry internal data). 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.
GeneDx	RCV002533148	SCV005439288	pathogenic	not provided	2024-06-14	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30442762, 29469822)