Submissions for variant NM_006767.4(LZTR1):c.2462T>C (p.Ile821Thr)

gnomAD frequency: 0.00001  dbSNP: rs1275511136

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV003133592	SCV003815342	uncertain significance	not provided	2021-03-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003133592	SCV004283861	uncertain significance	not provided	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 821 of the LZTR1 protein (p.Ile821Thr). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 29469822). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 635756). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LZTR1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LZTR1 function (PMID: 30481304). 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989603	SCV004806662	uncertain significance	LZTR1-related schwannomatosis	2024-03-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004559650	SCV005047888	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-07-21	criteria provided, single submitter	clinical testing	The p.I821T variant (also known as c.2462T>C), located in coding exon 21 of the LZTR1 gene, results from a T to C substitution at nucleotide position 2462. The isoleucine at codon 821 is replaced by threonine, an amino acid with similar properties. This alteration was identified in the homozygous state in two siblings diagnosed with Noonan syndrome (Johnston JJ et al. Genet Med, 2018 Oct;20:1175-1185). Functional studies indicate that this alteration had more diffuse subcellular localization compared to wild-type (Motta M et al. Hum. Mol. Genet., 2019 03;28:1007-1022). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003133592	SCV005081070	likely pathogenic	not provided	2024-05-17	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect of aberrant subcellular localization (PMID: 30481304); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29469822, 30481304)
Centre for Human Genetics	RCV004698789	SCV005200527	uncertain significance	Noonan syndrome 1		criteria provided, single submitter	clinical testing	This variant is predicted to be deleterious by in silico analysis. However, due to lack of experimental evidence demonstrating its impact on protein function, the clinical significance of this variant is currently uncertain.
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	RCV000787273	SCV000926202	uncertain significance	Noonan syndrome 2	2019-05-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535916	SCV004717318	uncertain significance	LZTR1-related disorder	2024-02-14	no assertion criteria provided	clinical testing	The LZTR1 c.2462T>C variant is predicted to result in the amino acid substitution p.Ile821Thr. This variant was reported in the homozygous state in two siblings with Noonan syndrome, while both heterozygous carrier parents were reported unaffected (Family 12, Johnston et al. 2018. PubMed ID: 29469822). Functional studies showed that this variant altered subcellular localization (Motta et al. 2019. PubMed ID: 30481304). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/635756/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.