Submissions for variant NM_006767.4(LZTR1):c.988A>G (p.Ser330Gly)

gnomAD frequency: 0.00005  dbSNP: rs777443417

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001320353	SCV001511135	uncertain significance	not provided	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 330 of the LZTR1 protein (p.Ser330Gly). This variant is present in population databases (rs777443417, gnomAD 0.03%). 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: 1020726). 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.
Ambry Genetics	RCV002384411	SCV002695810	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-11-20	criteria provided, single submitter	clinical testing	The c.988A>G (p.S330G) alteration is located in coding exon 9 of the LZTR1 gene. This alteration results from a A to G substitution at nucleotide position 988, causing the serine (S) at amino acid position 330 to be replaced by a glycine (G). Based on data from gnomAD, the G allele has an overall frequency of 0.002% (3/154198) total alleles studied. The highest observed frequency was 0.023% (2/8732) of African alleles. This variant was reported in a fetus with hydrops fetalis and hydrothorax that resolved in the third trimester; the infant was later diagnosed with EEC3 due to a pathogenic TP63 mutation and did not meet clinical diagnostic criteria for Noonan syndrome (Hurni, 2021). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325229	SCV004031138	uncertain significance	Noonan syndrome 10	2023-08-18	criteria provided, single submitter	clinical testing	The LZTR1 c.988A>G (p.Ser330Gly) missense change has a maximum frequency of 0.023% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported as compound heterozygous with a second LZTR1 variant of uncertain significance in a fetus with hydrops fetalis and hydrothorax that also harbored a pathogenic de novo variant in TP63. The infant was later diagnosed with ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3) and did not meet the diagnostic criteria for Noonan syndrome or present with any cardiac abnormalities (PMID: 34401172, 34906519). 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	RCV003462892	SCV004193644	uncertain significance	Schwannomatosis 2	2024-03-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001320353	SCV005080395	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a fetus with fetal hydrops and increased nuchal translucency, who also harbored a de novo pathogenic TP63 variant (Hurni et al., 2021; Marangoni et al., 2021); This variant is associated with the following publications: (PMID: 34906519, 34401172)