Submissions for variant NM_006767.4(LZTR1):c.2190C>T (p.Gly730=)

gnomAD frequency: 0.00034  dbSNP: rs144092577

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000877317	SCV001020036	likely benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328421	SCV001519543	benign	not specified	2021-03-11	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.2190C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 250542 control chromosomes, predominantly at a frequency of 0.00032 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 64 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 a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.2190C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000877317	SCV001793996	uncertain significance	not provided	2024-01-04	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000877317	SCV002009532	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002416082	SCV002725362	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2020-08-19	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000877317	SCV005410205	uncertain significance	not provided	2024-01-24	criteria provided, single submitter	clinical testing	PP3
PreventionGenetics, part of Exact Sciences	RCV004530868	SCV004112794	uncertain significance	LZTR1-related disorder	2024-04-18	no assertion criteria provided	clinical testing	The LZTR1 c.2190C>T variant is not predicted to result in an amino acid change (p.=). This variant is predicted to create a cryptic donor splice site based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). However, the use of computer prediction programs is not equivalent to functional evidence. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common for autosomal dominant Noonan syndrome (Gelb et al. 2018. PubMed ID 29493581). In ClinVar, it has conflicting interpretations of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/706636/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.