ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413889 SCV000491461 pathogenic not provided 2018-09-11 criteria provided, single submitter clinical testing The G248R variant in the LZTR1 gene has been reported previously in an individual with a clinical diagnosis of Noonan syndrome, as well as in that individual’s affected mother and grandfather (Yamamoto et al., 2015). The G248R variant is not observed in large population cohorts (Lek et al., 2016). The G248R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within Kelch domain 4 that is conserved across species (UniProt Consortium, 2015). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant has been identified as de novo with confirmed parentage in a patient with a LZTR1-related disorder previously tested at GeneDx. We interpret G248R as a pathogenic variant.
Ambry Genetics RCV000623699 SCV000743074 likely pathogenic Inborn genetic diseases 2017-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
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 2019-12-12 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.
Integrated Genetics/Laboratory Corporation of America 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.
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.

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