Submissions for variant NM_006767.4(LZTR1):c.2468C>T (p.Ser823Phe)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002450589	SCV002733894	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2021-12-13	criteria provided, single submitter	clinical testing	The p.S823F variant (also known as c.2468C>T), located in coding exon 21 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2468. The serine at codon 823 is replaced by phenylalanine, an amino acid with highly dissimilar 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	RCV003101853	SCV003481885	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	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. This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 823 of the LZTR1 protein (p.Ser823Phe). This variant is present in population databases (rs764779655, gnomAD 0.002%). 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: 1791716). 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.
Baylor Genetics	RCV003475385	SCV004193610	uncertain significance	Schwannomatosis 2	2023-07-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479427	SCV004223059	uncertain significance	not specified	2023-11-21	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.2468C>T (p.Ser823Phe) 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 4e-06 in 250908 control chromosomes (gnomAD). 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.2468C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.