ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.1591G>A (p.Asp531Asn)

gnomAD frequency: 0.00003  dbSNP: rs138615487
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001758313 SCV001986415 uncertain significance not provided 2023-11-15 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30859559, 36252119)
Labcorp Genetics (formerly Invitae), Labcorp RCV001758313 SCV002257942 uncertain significance not provided 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 531 of the LZTR1 protein (p.Asp531Asn). This variant is present in population databases (rs138615487, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of autosomal recessive Noonan syndrome (PMID: 30859559, 36252119). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1304020). 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 RCV002405292 SCV002708975 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2024-01-04 criteria provided, single submitter clinical testing The p.D531N variant (also known as c.1591G>A), located in coding exon 14 of the LZTR1 gene, results from a G to A substitution at nucleotide position 1591. The aspartic acid at codon 531 is replaced by asparagine, an amino acid with highly similar properties. Exome sequencing of 9624 patients from the Deciphering Developmental Disorders (DDDs) study identified this variant in trans with a LZTR1 truncating mutation in one proband (Pagnamenta AT et al. Clin. Genet., 2019 06;95:693-703). This amino acid position is highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003230694 SCV003928309 uncertain significance not specified 2024-01-15 criteria provided, single submitter clinical testing Variant summary: LZTR1 c.1591G>A (p.Asp531Asn) results in a conservative amino acid change located in the BTB/POZ domain (IPR000210) of 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 2.6e-05 in 233862 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1591G>A has been reported in the literature in at least one compound heterozygous individual affected with Noonan Syndrome 2 (e.g., Pagnamenta_2019) and one compound heterozygous pediatric hypertrophic cardiomyopathy patient (e.g., Bagnall_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30859559, 36252119). ClinVar contains an entry for this variant (Variation ID: 1304020). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics RCV004571075 SCV005060597 uncertain significance Schwannomatosis 2 2024-03-25 criteria provided, single submitter clinical testing

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