Submissions for variant NM_006767.4(LZTR1):c.23G>C (p.Gly8Ala)

gnomAD frequency: 0.00004  dbSNP: rs764439278

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201227	SCV001372319	uncertain significance	not specified	2025-03-31	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.23G>C (p.Gly8Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.7e-05 in 163164 control chromosomes. Although present at a frequency exceeding that of Autosomal Dominant Noonan Syndrome And Related Conditions, this frequency is not significantly higher than estimated for a pathogenic variant causing Autosomal Recessive LZTR1 causing Noonan Syndrome 2 (6.7e-05 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.23G>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: 933179). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859216	SCV002129071	uncertain significance	not provided	2025-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 8 of the LZTR1 protein (p.Gly8Ala). This variant is present in population databases (rs764439278, gnomAD 0.04%). 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: 933179). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV002447045	SCV002732029	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Baylor Genetics	RCV003469318	SCV004191307	uncertain significance	LZTR1-related schwannomatosis	2024-03-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001859216	SCV005332903	uncertain significance	not provided	2024-03-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with features of growth hormone insensitivity and Noonan syndrome (PMID: Chatterjee2019[Abstract]); This variant is associated with the following publications: (PMID: Chatterjee2019[Abstract])