Submissions for variant NM_006767.4(LZTR1):c.791+1G>T

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002416692	SCV002676520	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-12-12	criteria provided, single submitter	clinical testing	The c.791+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 8 of the LZTR1 gene. 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). 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). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this variant is likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003103453	SCV003472979	pathogenic	not provided	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 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 is present in population databases (rs148031742, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with clinical features of LZTR1-related conditions (PMID: 25335493, 28295212; internal data). ClinVar contains an entry for this variant (Variation ID: 1761188). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003471360	SCV004191213	likely pathogenic	LZTR1-related schwannomatosis	2023-10-19	criteria provided, single submitter	clinical testing
GeneDx	RCV003103453	SCV005371741	likely pathogenic	not provided	2024-02-05	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24362817, 28295212, 25480913, 29469822, 30859559, 30442766, 30368668, 25795793, 25335493, 30442762, 30481304)