Submissions for variant NM_006767.4(LZTR1):c.946G>A (p.Val316Met)

gnomAD frequency: 0.00004  dbSNP: rs370315661

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420965	SCV001623444	uncertain significance	not specified	2021-05-17	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.946G>A (p.Val316Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5e-05 in 158726 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.946G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001806178	SCV002050355	uncertain significance	not provided	2023-10-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002449141	SCV002683226	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-02	criteria provided, single submitter	clinical testing	The p.V316M variant (also known as c.946G>A), located in coding exon 9 of the LZTR1 gene, results from a G to A substitution at nucleotide position 946. The valine at codon 316 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001806178	SCV003028451	uncertain significance	not provided	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 316 of the LZTR1 protein (p.Val316Met). This variant is present in population databases (rs370315661, gnomAD 0.02%). 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: 1098836). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003154035	SCV003843042	uncertain significance	Noonan syndrome 10	2022-01-06	criteria provided, single submitter	clinical testing	The LZTR1 c.946G>A (p.Val316Met) missense change has a maximum frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. 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.
Baylor Genetics	RCV003470846	SCV004191223	uncertain significance	Schwannomatosis 2	2023-10-16	criteria provided, single submitter	clinical testing
3billion	RCV004728717	SCV005328917	likely benign	Noonan syndrome 2	2024-09-20	criteria provided, single submitter	clinical testing	The homozygous variant was found in patients diagnosed with another variant in a different gene, with no symptoms related to the gene containing the homozygous variant.