ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.2173C>T (p.Arg725Cys)

gnomAD frequency: 0.00002  dbSNP: rs778626874
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV001337007 SCV001530561 uncertain significance Noonan syndrome 10 2018-05-03 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001813590 SCV002060791 uncertain significance Noonan syndrome and Noonan-related syndrome 2020-10-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV002431943 SCV002730558 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-12-22 criteria provided, single submitter clinical testing The p.R725C variant (also known as c.2173C>T), located in coding exon 18 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2173. The arginine at codon 725 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was detected in a cohort of over 11,730 samples from patients with neurodevelopmental disorders (NDDs) from international clinical and research cohorts (Stessman HA et al. Nat Genet, 2017 Apr;49:515-526). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003442854 SCV004168292 uncertain significance not provided 2023-04-26 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individual(s) with autism, intellectual disability, and/or developmental delay (Stessman et al., 2017); This variant is associated with the following publications: (PMID: 28191889)
Labcorp Genetics (formerly Invitae), Labcorp RCV003442854 SCV004455414 uncertain significance not provided 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 725 of the LZTR1 protein (p.Arg725Cys). This variant is present in population databases (rs778626874, gnomAD 0.02%). This missense change has been observed in individual(s) with neurodevelopmental delay (PMID: 28191889). ClinVar contains an entry for this variant (Variation ID: 1034312). 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.

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