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

gnomAD frequency: 0.00002  dbSNP: rs769001939

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314262	SCV001504789	uncertain significance	not provided	2025-01-29	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). 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%. 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	LZTR1-related schwannomatosis	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	2024-11-21	criteria provided, single submitter	clinical testing	The c.353G>A (p.R118H) alteration is located in exon 4 (coding exon 4) of the LZTR1 gene. This alteration results from a G to A substitution at nucleotide position 353, causing the arginine (R) at amino acid position 118 to be replaced by a histidine (H). 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. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (5/251060) total alleles studied. The highest observed frequency was 0.007% (2/30616) of South Asian alleles. This mutation has been detected in multiple individuals with schwannomas; three of the schwannomas showed somatic events consistent with schwannomatosis (Louvrier, 2018; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002225132	SCV002768086	likely pathogenic	LZTR1-related schwannomatosis	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	LZTR1-related schwannomatosis	2024-01-26	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV005232261	SCV005872376	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing	Classification criteria: PP3_Moderate