Submissions for variant NM_006767.4(LZTR1):c.1700G>A (p.Arg567His)

dbSNP: rs372417941

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243402	SCV001416559	uncertain significance	not provided	2025-01-06	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 567 of the LZTR1 protein (p.Arg567His). This variant is present in population databases (rs372417941, gnomAD 0.05%). 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: 968299). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290606	SCV001478700	likely benign	not specified	2021-01-07	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.1700G>A (p.Arg567His) results in a non-conservative amino acid change located in the BTB/POZ domain (IPR000210) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.9e-05 in 251506 control chromosomes (gnomAD and publication data). The observed variant frequency is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in LZTR1 causing Noonan Syndrome phenotype (5e-06), strongly suggesting that the variant is benign. c.1700G>A has been reported in the literature in one individual affected with D-Bifunctional protein deficiency as well as in one control (Kanchi_2014, Matsukawa_2016). These reports do not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001243402	SCV001766955	uncertain significance	not provided	2024-08-06	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed in any cases, but was observed in unaffected controls from an ovarian cancer case-control study (PMID: 24448499); This variant is associated with the following publications: (PMID: 28017249, 24448499)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291738	SCV002584764	uncertain significance	LZTR1-related schwannomatosis	2022-07-26	criteria provided, single submitter	clinical testing	The LZTR1 c.1700G>A (p.Arg567His) missense change has a maximum subpopulation frequency of 0.045% 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.
Ambry Genetics	RCV002402775	SCV002710151	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-08-10	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.
Genetics and Molecular Pathology, SA Pathology	RCV002466649	SCV002761586	uncertain significance	Noonan syndrome 10	2020-03-02	criteria provided, single submitter	clinical testing