ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.742G>A (p.Gly248Arg) (rs869320686)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413889 SCV000491461 pathogenic not provided 2021-10-01 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect due to upregulation of the RAS-MAPK signaling pathway (Motta et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26446362, 27942422, 31533111, 23917401, 25795793, 28944487, 30481304, 28991257, 30368668, 31324109, 30859559, 31825158, 32981126)
Ambry Genetics RCV000623699 SCV000743074 pathogenic Inborn genetic diseases 2017-10-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763072 SCV000893582 likely pathogenic Schwannomatosis 2; Noonan syndrome 10 2018-10-31 criteria provided, single submitter clinical testing
Genetics Molecular Biology Lab, Hospital Juan P Garrahan RCV000191027 SCV000920884 pathogenic Noonan syndrome 10 criteria provided, single submitter clinical testing
Invitae RCV000413889 SCV001229241 pathogenic not provided 2019-12-05 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 248 of the LZTR1 protein (p.Gly248Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) and families with Noonan syndrome (PMID: 25795793, 30368668, 30859559). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 209088). This variant has been reported to affect LZTR1 protein function (PMID: 30481304). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175007 SCV001338505 pathogenic Rasopathy 2020-04-10 criteria provided, single submitter clinical testing Variant summary: LZTR1 c.742G>A (p.Gly248Arg) results in a non-conservative amino acid change located in the Kelch repeat type 1 (IPR006652) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251070 control chromosomes (gnomAD). c.742G>A has been reported in the literature in multiple individuals (including familial and de novo cases) affected with Noonan Syndrome And Related Conditions (e.g. Clinton_2020, Umeki_2019, Yamamoto_2015). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to result in increased RAS activation and upregulation of the MAPK pathway, consistent with a gain-of-function molecular mechanism of disease (Bigenzahn_2018, Motta_2019). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000191027 SCV001439375 pathogenic Noonan syndrome 10 2020-09-03 criteria provided, single submitter research ACMG codes:PS3, PS4M, PM1, PM2, PP3
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001287567 SCV001474269 pathogenic none provided 2020-05-28 criteria provided, single submitter clinical testing The LZTR1 c.742G>A; p.Gly248Arg variant (rs869320686) is reported in the literature in individuals with Noonan syndrome (Umeki 2018, Jin 2017), is reported to segregate with disease (Yamamoto 2015), and is reported as occurring de novo in some affected individuals (Pagnamenta 2019). The variant is reported as pathogenic or likely pathogenic by several sources in the ClinVar database (Variation ID: 209088) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 248 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, this variant occurs in the Kelch functional domain and transfected variant protein results in enhanced ERK1/2 photphorylation (Motta 2019). Considering available information, this variant is classified as pathogenic. References: Jin SC et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet. 2017 Nov;49(11):1593-1601. Motta M et al. Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. Hum Mol Genet. 2019 Mar 15;28(6):1007-1022. Pagnamenta AT et al. Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome. Clin Genet. 2019 Jun;95(6):693-703. Umeki I et al. Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. Hum Genet. 2019 Jan;138(1):21-35. Yamamoto GL et al. Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. J Med Genet. 2015 Jun;52(6):413-21.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001526613 SCV001737043 pathogenic Fetal cystic hygroma criteria provided, single submitter clinical testing
OMIM RCV000191027 SCV000246007 pathogenic Noonan syndrome 10 2015-06-01 no assertion criteria provided literature only
GenomeConnect, ClinGen RCV000191027 SCV001423246 not provided Noonan syndrome 10 no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 01-22-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000413889 SCV001741682 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000413889 SCV001953290 pathogenic not provided no assertion criteria provided clinical testing
PerkinElmer Genomics RCV000413889 SCV002017208 pathogenic not provided 2021-02-24 no assertion criteria provided clinical testing

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