Submissions for variant NM_006767.4(LZTR1):c.989G>T (p.Ser330Ile)

gnomAD frequency: 0.00003  dbSNP: rs376331457

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420772	SCV001623123	uncertain significance	not specified	2021-05-02	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.989G>T (p.Ser330Ile) 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 6.5e-06 in 154000 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.989G>T 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859334	SCV002205283	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 330 of the LZTR1 protein (p.Ser330Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1098763). 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. 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.
Ambry Genetics	RCV002384623	SCV002693263	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-12-07	criteria provided, single submitter	clinical testing	The p.S330I variant (also known as c.989G>T), located in coding exon 9 of the LZTR1 gene, results from a G to T substitution at nucleotide position 989. The serine at codon 330 is replaced by isoleucine, an amino acid with 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.
Revvity Omics, Revvity	RCV001859334	SCV003815343	uncertain significance	not provided	2021-08-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463042	SCV004193650	uncertain significance	Schwannomatosis 2	2024-03-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003463042	SCV004806657	uncertain significance	Schwannomatosis 2	2024-03-26	criteria provided, single submitter	clinical testing