ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.842C>T (p.Pro281Leu) (rs1390048261)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000681035 SCV000808488 uncertain significance not provided 2017-07-26 criteria provided, single submitter clinical testing The P281L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P281L variant is not observed in large population cohorts (Lek et al., 2016). The P281L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000681035 SCV001153628 uncertain significance not provided 2018-12-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193027 SCV001361561 uncertain significance not specified 2021-05-26 criteria provided, single submitter clinical testing Variant summary: LZTR1 c.842C>T (p.Pro281Leu) results in a non-conservative amino acid change located in one of the kelch repeats (IPR006652) of the encoded protein sequence. Five 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 150946 control chromosomes (gnomAD v3.1 genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.842C>T has been reported in the literature in an individual affected with schwannomatosis (Louvrier_2018). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV001266041 SCV001444213 uncertain significance Inborn genetic diseases 2019-10-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV001330298 SCV001521939 uncertain significance Noonan syndrome 10 2020-02-05 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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