Submissions for variant NM_006767.4(LZTR1):c.1855C>T (p.Arg619Cys)

gnomAD frequency: 0.00007  dbSNP: rs373488966

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000681434	SCV000808897	uncertain significance	not provided	2024-09-27	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000681434	SCV001471456	uncertain significance	not provided	2020-05-29	criteria provided, single submitter	clinical testing	The LZTR1 c.1855C>T; p.Arg619Cys variant (rs373488966), to our knowledge, is not reported in the medical literature or gene specific databases. The variant is listed in the ClinVar database (Variation ID: 561973) and in the general population with an overall allele frequency of 0.004% (11/282,526 alleles) in the Genome Aggregation Database. The arginine at codon 619 is moderately conserved and computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.Arg619Cys variant is uncertain at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681434	SCV002261005	uncertain significance	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 619 of the LZTR1 protein (p.Arg619Cys). This variant is present in population databases (rs373488966, gnomAD 0.009%). 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: 561973). 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.
Institute of Human Genetics, University Hospital Muenster	RCV004584403	SCV002577900	uncertain significance	See cases	2021-12-20	criteria provided, single submitter	clinical testing	ACMG categories: PP6
Ambry Genetics	RCV002406527	SCV002722103	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-11-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004559347	SCV005047098	uncertain significance	Noonan syndrome 2; Noonan syndrome 10	2024-04-02	criteria provided, single submitter	clinical testing	An LZTR1 c.18553C>T (p.Arg619Cys) variant was identified at a near heterozygous allelic fraction consistent with germline origin. This variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline variant of uncertain significance by multiple submitters (ClinVar ID: 561973). This variant is only observed on 82/1,613,234 alleles in the general population (gnomAD v.4.0.0), indicating it is not a common variant. Computational predictors suggest that the variant does not impact LZTR1 function. Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
Baylor Genetics	RCV004568579	SCV005060590	uncertain significance	LZTR1-related schwannomatosis	2024-03-29	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004788107	SCV005402168	uncertain significance	Noonan syndrome 10	2023-12-25	criteria provided, single submitter	clinical testing	The LZTR1 c.1855C>T (p.Arg619Cys) missense change has a maximum frequency of 0.008% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Noonan syndrome or schwannomatosis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.