ClinVar Miner

Submissions for variant NM_004525.3(LRP2):c.2603C>G (p.Thr868Ser)

gnomAD frequency: 0.00100  dbSNP: rs150752263
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000117520 SCV000151738 uncertain significance not provided 2014-03-13 criteria provided, single submitter clinical testing
Invitae RCV000117520 SCV001050891 likely benign not provided 2021-12-08 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000117520 SCV001152552 uncertain significance not provided 2016-10-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001134613 SCV001294364 likely benign Donnai-Barrow syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx RCV000117520 SCV001759326 uncertain significance not provided 2020-01-21 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30900415)
Genome-Nilou Lab RCV001134613 SCV002055667 uncertain significance Donnai-Barrow syndrome 2021-07-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002271409 SCV002555927 likely benign not specified 2022-06-16 criteria provided, single submitter clinical testing Variant summary: LRP2 c.2603C>G (p.Thr868Ser) results in a conservative amino acid change located in the LDLR class B repeat (IPR000033) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 282278 control chromosomes (gnomAD), predominantly at a frequency of 0.0064 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 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in LRP2 causing Donnai Barrow Syndrome (0.0011), 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.2603C>G in individuals affected with Donnai Barrow Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: four classified the variant as of uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252555 SCV001428312 uncertain significance Intellectual disability 2019-01-01 no assertion criteria provided clinical testing

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