Submissions for variant NM_006767.4(LZTR1):c.2063G>A (p.Arg688His)

gnomAD frequency: 0.00002  dbSNP: rs535779363

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000788505	SCV000927650	uncertain significance	not provided	2018-04-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000788505	SCV002135848	uncertain significance	not provided	2023-11-01	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 688 of the LZTR1 protein (p.Arg688His). This variant is present in population databases (rs535779363, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of schwannomatosis (PMID: 30442762). ClinVar contains an entry for this variant (Variation ID: 636620). 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.
Ambry Genetics	RCV002422674	SCV002724850	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-10-27	criteria provided, single submitter	clinical testing	The p.R688H variant (also known as c.2063G>A), located in coding exon 17 of the LZTR1 gene, results from a G to A substitution at nucleotide position 2063. The arginine at codon 688 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in individuals with schwannomatosis (Steklov M et al. Science, 2018 12;362:1177-1182; Louvrier C et al. Neuro Oncol, 2018 Jun;20:917-929). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000788505	SCV003815335	uncertain significance	not provided	2021-12-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000788505	SCV003919301	uncertain significance	not provided	2022-10-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with schwannomatosis in published literature (Steklov et al., 2018); This variant is associated with the following publications: (PMID: 30442762)
Baylor Genetics	RCV003472326	SCV004191311	uncertain significance	Schwannomatosis 2	2024-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004768650	SCV005380745	uncertain significance	not specified	2024-08-09	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.2063G>A (p.Arg688His) results in a non-conservative amino acid change located in the BTB/POZ domain (IPR000210) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247878 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2063G>A has been reported in the literature in individuals affected with Schwannomatosis or with clinical features of Noonan syndrome, all without evidence of causality (e.g. Steklov_2018, Louvrier_2018, Almubarak_2022). These reports do not provide unequivocal conclusions about association of the variant with Schwannomatosis or Noonan syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36360262, 29409008, 30442762). ClinVar contains an entry for this variant (Variation ID: 636620). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004735801	SCV005361654	uncertain significance	LZTR1-related disorder	2024-09-19	no assertion criteria provided	clinical testing	The LZTR1 c.2063G>A variant is predicted to result in the amino acid substitution p.Arg688His. This variant was reported in an individual with Schwannomatosis (Steklov et al. 2018. PubMed ID: 30442762; Table S8 Louvrier et al. 2018. PMID: 29409008). Alternative variants at the same codon p.Arg688Cys has bee also observed in an individual with Schwannomatosis (Figure 3A, Steklov et al. 2018. PubMed ID: 30442762; Piotrowski et al. 2014. PubMed ID: 24362817) and p.Arg688Gly in an individual with Noonan syndrome (Figure 3A, Steklov et al. 2018. PubMed ID: 30442762). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/636620/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.