ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.353G>A (p.Arg118His)

gnomAD frequency: 0.00002  dbSNP: rs769001939
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001314262 SCV001504789 uncertain significance not provided 2023-12-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 118 of the LZTR1 protein (p.Arg118His). This variant is present in population databases (rs769001939, 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: 1015410). 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%. 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.
Molecular Genetics, Royal Melbourne Hospital RCV002225132 SCV002503812 likely pathogenic Schwannomatosis 2 2020-07-29 criteria provided, single submitter clinical testing This sequence change is predicted to replace arginine with histidine at codon 118 of the LZTR1 protein (p.Arg118His). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located within the Kelch 1 repeat domain, a highly conserved region amongst vertebrates. There is a small physicochemical difference between arginine and histidine. The variant is present in a large population cohort at a frequency of 0.002% (rs769001939, 5/251,060 alleles, 0 homozygotes, gnomAD v2.1). It has been reported in heterozygous form in five unrelated probands with schwannomatosis (PMID: 29409008, 31370276). Taken together, the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in a non-neurological disease control cohort (PS4; gnomAD non-neuro v2.1, PMID: 29409008). Tumour samples from these probands showed specific somatic changes (loss of heterozygosity of LZTR1 and a pathogenic variant in NF2) consistent with the molecular profile of schwannomas (PP4; PMID: 29409008). Multiple lines of computational evidence predict a deleterious effect for this missense substitution (PP3; 5/5 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP3, PP4, PS4.
Ambry Genetics RCV002456412 SCV002617278 pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-03-23 criteria provided, single submitter clinical testing The p.R118H pathogenic mutation (also known as c.353G>A), located in coding exon 4 of the LZTR1 gene, results from a G to A substitution at nucleotide position 353. The arginine at codon 118 is replaced by histidine, an amino acid with highly similar properties. This mutation has been detected in multiple individuals with schwannomas; three of the schwannomas showed somatic events consistent with schwannomatosis (Louvrier C et al. Neuro Oncol, 2018 06;20:917-929; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is pathogenic for an increased risk of LZTR1-related schwannomatosis (SWN). This alteration is also likely to cause autosomal recessive Noonan syndrome when present along with a second pathogenic variant on the other allele; however, the clinical significance for autosomal dominant Noonan syndrome is unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002225132 SCV002768086 likely pathogenic Schwannomatosis 2 2022-02-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with Noonan syndrome 10 (MIM#616564). Missense variants in this gene enhance stimulus-dependent RAS-MAPK signaling, consistent with lost LZTR1 function as a negative regulator of this pathway (PMID: 30481304). Susceptibility to schwannomatosis-2 (MIM#615670) requires a somatic second hit and is the result of a loss of function mechanism (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance; however, this is only applicable to schwannomatosis (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity; however, this is only applicable to schwannomatosis (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytosine-phosphate-guanine motif (PMID: 29409008). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS (LOVD, ClinVar), but has also been observed in at least six unrelated individuals with schwannomatosis and described as likely pathogenic (PMID: 31370276, PMID: 29409008). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
CeGaT Center for Human Genetics Tuebingen RCV001314262 SCV004703353 uncertain significance not provided 2024-01-01 criteria provided, single submitter clinical testing LZTR1: PM2:Supporting, PP3, PP4, PS4:Supporting
Baylor Genetics RCV002225132 SCV005060655 uncertain significance Schwannomatosis 2 2024-01-26 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.