ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.1888C>T (p.Arg630Trp)

dbSNP: rs750813513
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001786618 SCV002028474 uncertain significance not provided 2023-06-09 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; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001786618 SCV002230607 uncertain significance not provided 2023-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 630 of the LZTR1 protein (p.Arg630Trp). This variant is present in population databases (rs750813513, gnomAD 0.003%). 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: 1326438). 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 RCV002406884 SCV002722464 uncertain significance Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2023-01-18 criteria provided, single submitter clinical testing The p.R630W variant (also known as c.1888C>T), located in coding exon 16 of the LZTR1 gene, results from a C to T substitution at nucleotide position 1888. The arginine at codon 630 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004536314 SCV004117281 uncertain significance LZTR1-related disorder 2023-07-19 criteria provided, single submitter clinical testing The LZTR1 c.1888C>T variant is predicted to result in the amino acid substitution p.Arg630Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-21349261-C-T). In ClinVar, this variant is currently listed as 'uncertain significance' by outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/1326438/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV003470917 SCV004191263 uncertain significance LZTR1-related schwannomatosis 2023-09-13 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004785312 SCV005398293 uncertain significance Noonan syndrome 2 2024-10-08 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive Noonan syndrome 2 (MIM#605275); dominant negative is the mechanism suspected for autosomal dominant Noonan syndrome 10 (MIM#616564) (ClinGen). (I) 0108 - This gene is associated with both recessive and dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygote(s), 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (highest allele count in v2: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg630Gln) has been reported as a VUS by multiple clinical testing laboratories, and as likely pathogenic by a clinical testing laboratory (ClinVar). p.(Arg630Pro) has been reported as a VUS by a clinical testing laboratory (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS by multiple clinical testing laboratories (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV005023257 SCV005656762 uncertain significance Noonan syndrome 2; LZTR1-related schwannomatosis; Noonan syndrome 10 2024-06-21 criteria provided, single submitter clinical testing

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