ClinVar Miner

Submissions for variant NM_006767.4(LZTR1):c.594-3C>T

gnomAD frequency: 0.00015  dbSNP: rs373968693
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264472 SCV001442646 likely benign not specified 2020-10-19 criteria provided, single submitter clinical testing Variant summary: LZTR1 c.594-3C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00015 in 250884 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 400 fold of the estimated maximal expected allele frequency for a pathogenic variant in LZTR1 causing Noonan Syndrome phenotype (5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.594-3C>T in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics RCV001330296 SCV001521937 uncertain significance Noonan syndrome 2 2019-08-17 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae RCV001401433 SCV001603256 likely benign not provided 2024-01-27 criteria provided, single submitter clinical testing
GeneDx RCV001401433 SCV001751986 likely benign not provided 2018-07-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV002357064 SCV002647606 benign Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2021-10-28 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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