Submissions for variant NM_006767.4(LZTR1):c.488C>T (p.Thr163Met)

gnomAD frequency: 0.00014  dbSNP: rs200806641

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001203002	SCV001374144	uncertain significance	not provided	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 163 of the LZTR1 protein (p.Thr163Met). This variant is present in population databases (rs200806641, 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: 934586). 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.
GeneDx	RCV001203002	SCV001813593	uncertain significance	not provided	2023-06-05	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
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813580	SCV002060778	uncertain significance	Noonan syndrome and Noonan-related syndrome	2020-10-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002339507	SCV002638758	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-08-19	criteria provided, single submitter	clinical testing	The p.T163M variant (also known as c.488C>T), located in coding exon 5 of the LZTR1 gene, results from a C to T substitution at nucleotide position 488. The threonine at codon 163 is replaced by methionine, an amino acid with similar properties. This amino acid position is well 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.
Baylor Genetics	RCV003469324	SCV004191207	uncertain significance	Schwannomatosis 2	2023-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003490116	SCV004241575	likely benign	not specified	2023-12-21	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.488C>T (p.Thr163Met) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 251218 control chromosomes. The observed variant frequency is approximately 19-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. To our knowledge, no occurrence of c.488C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.