Submissions for variant NM_006767.4(LZTR1):c.1666A>G (p.Ser556Gly)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002403893	SCV002706589	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-12-18	criteria provided, single submitter	clinical testing	The c.1666A>G variant (also known as p.S556G), located in coding exon 15 of the LZTR1 gene, results from an A to G substitution at nucleotide position 1666. The serine at codon 556 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in the compound heterozygous state in conjunction with a pathogenic LZTR1 truncation in a patient with features of Noonan syndrome (Mena R et al. Am J Med Genet C Semin Med Genet, 2020 12;184:996-1008). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003097085	SCV003245097	uncertain significance	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 556 of the LZTR1 protein (p.Ser556Gly). This variant is not present in population databases (gnomAD no frequency). 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: 1777571). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LZTR1 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV003097085	SCV003815332	uncertain significance	not provided	2019-08-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003464530	SCV004193681	uncertain significance	Schwannomatosis 2	2023-03-19	criteria provided, single submitter	clinical testing