Submissions for variant NM_006767.4(LZTR1):c.2507T>C (p.Leu836Pro)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002434909	SCV002745113	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-06-24	criteria provided, single submitter	clinical testing	The p.L836P variant (also known as c.2507T>C), located in coding exon 21 of the LZTR1 gene, results from a T to C substitution at nucleotide position 2507. The leucine at codon 836 is replaced by proline, 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	RCV003465760	SCV004191222	uncertain significance	LZTR1-related schwannomatosis	2024-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003720630	SCV004508508	uncertain significance	not provided	2024-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 836 of the LZTR1 protein (p.Leu836Pro). This variant is present in population databases (rs150100732, gnomAD 0.003%). 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: 1792330). 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	RCV004801214	SCV005422337	uncertain significance	not specified	2024-10-14	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.2507T>C (p.Leu836Pro) results in a non-conservative amino acid change in 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 1.2e-05 in 250146 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.2507T>C in individuals affected with Noonan Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1792330). Based on the evidence outlined above, the variant was classified as uncertain significance.