ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.1084C>T (p.Arg362Ter) (rs189150283)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000329167 SCV000344439 pathogenic not provided 2016-08-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763074 SCV000893584 pathogenic Schwannomatosis 2; Noonan syndrome 10 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193024 SCV001361558 likely pathogenic Schwannomatosis 2019-11-25 criteria provided, single submitter clinical testing Variant summary: LZTR1 c.1084C>T (p.Arg362X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Germline loss of function mutations in LZTR1 have been reported to predispose to an inherited disorder of multiple schwannomas (Piotrowski_2014). The variant allele was found at a frequency of 6e-05 in 251042 control chromosomes (gnomAD). As a gene with a pLI score of 0 (gnomAD) this gene is expected to be tolerant to loss of function variants. Therefore, this frequency does not allow any conclusions about variant significance in relation to Schwannomatosis. The variant, c.1084C>T, has been reported in the literature in individuals affected with Schwannomatosis (Jordan_2018, Louvrier_2018) as well as one individual in the 1000 Genome cohort without phenotypic information (Piotrowski_2014) and in a sequencing study of healthy participants (Hou_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics,Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000736158 SCV000864455 pathogenic Short stature 2001-11-18 no assertion criteria provided case-control

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