ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.850C>T (p.Arg284Cys) (rs797045165)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658480 SCV000778847 pathogenic not provided 2018-01-18 criteria provided, single submitter clinical testing The R284C variant in the LZTR1 gene has been reported previously as a de novo variant with confirmed parentage in an individual with Noonan syndrome and several of her affected children and an apparently de novo variant an individual with schwannomatosis (Yamamoto et al., 2015; Paganini et al., 2015). The R284C variant is not observed in large population cohorts (Lek et al., 2016). The R284C 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 is located within the kelch 4 domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret R284C as a pathogenic variant. This variant was observed in individuals with clinical features consistent with a RASopathy. Clinical features observed in patients with this variant include developmental delay, nystagmus, ventricular septal defect, cryptorchidism, and/or astigmatism. This variant has been confirmed de novo in at least 1 individual tested at GeneDx.
Fulgent Genetics,Fulgent Genetics RCV000763073 SCV000893583 pathogenic Schwannomatosis 2; Noonan syndrome 10 2018-10-31 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000191028 SCV000996259 pathogenic Noonan syndrome 10 2019-03-01 criteria provided, single submitter clinical testing This variant has been previously reported as a heterozygous change in six related individuals with autosomal dominant Noonan Syndrome (PMID: 25795793) and as an apparently de novo change in an individual with schwannomatosis (PMID: 25335493). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. This variant has been classified as a de novo pathogenic variant for Noonan syndrome in ClinVar (Variation ID: 209089). In-silico analyses support a damaging effect of the c.850C>T (p.Arg284Cys) variant on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.850C>T (p.Arg284Cys) variant is classified as pathogenic.
OMIM RCV000191028 SCV000246008 pathogenic Noonan syndrome 10 2015-06-01 no assertion criteria provided literature only

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