ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.26G>C (p.Gly9Ala)

dbSNP: rs756485244
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001055587 SCV001219987 uncertain significance not provided 2024-01-30 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 9 of the LZTR1 protein (p.Gly9Ala). This variant is present in population databases (rs756485244, 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: 522164). 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 95%. 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 RCV001199922 SCV001370698 likely benign not specified 2020-05-04 criteria provided, single submitter clinical testing Variant summary: LZTR1 c.26G>C (p.Gly9Ala) 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 9.8e-05 in 163374 control chromosomes (gnomAD). The observed variant frequency is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in LZTR1 causing Noonan Syndrome And Related Conditions phenotype (5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.26G>C in individuals affected with Noonan Syndrome And Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV001199922 SCV002518656 benign not specified 2022-05-04 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002291680 SCV002584543 uncertain significance Noonan syndrome 10 2022-08-10 criteria provided, single submitter clinical testing The LZTR1 c.26G>C (p.Gly9Ala) missense change has a maximum subpopulation frequency of 0.038% 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. To our knowledge, this variant has not been reported in individuals with Noonan syndrome or Schwannomatosis. 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. 
Ambry Genetics RCV002438612 SCV002744868 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2022-10-27 criteria provided, single submitter clinical testing The p.G9A variant (also known as c.26G>C), located in coding exon 1 of the LZTR1 gene, results from a G to C substitution at nucleotide position 26. The glycine at codon 9 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001055587 SCV003805482 uncertain significance not provided 2023-02-20 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics RCV003465360 SCV004191208 uncertain significance Schwannomatosis 2 2024-02-11 criteria provided, single submitter clinical testing

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