ClinVar Miner

Submissions for variant NR_003051.3(RMRP):n.-25_-6dup

dbSNP: rs1554651445
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001057314 SCV001221800 pathogenic Anauxetic dysplasia 2023-07-06 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. While functional studies for this variant have not been reported, experimental analyses using patient derived cells, as well as in vitro transfection studies, have shown that promoter insertions result in silencing of RMRP transcription and reduced expression of the gene product (PMID: 11207361, 16254002). ClinVar contains an entry for this variant (Variation ID: 852657). While this particular variant has not been reported in the literature, it is located in the promoter region between the TATA box and the transcription initiation site, and other insertions and duplications immediately upstream of the coding sequence have been reported in individuals affected with cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders (PMID: 16244706, 11207361, 12107819). This variant is not present in population databases (gnomAD no frequency). This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001832519 SCV003934280 likely pathogenic Metaphyseal chondrodysplasia, McKusick type 2023-05-23 criteria provided, single submitter clinical testing Variant summary: RMRP n.-25_-6dup20 involves the insertion of 20 nucleotides in the promoter region of RMRP, which is located between the TATA box (-33 to -25) and the transcription initiation site. Other insertions or duplications in the promoter region of RMRP have been classified as pathogenic (internally and in ClinVar). The variant was absent in 127922 control chromosomes. To our knowledge, no occurrence of n.-25_-6dup20 in individuals affected with Cartilage-Hair Hypoplasia and no experimental evidence demonstrating its impact on protein function have been reported. However, many other insertions or duplications in the promoter region of RMRP have been reported in affected individuals in the literature (e.g. PMIDs: 21956908, 21396580, 11207361, 16244706) and have been demonstrated through functional studies to lead to reduced RMRP transcription (e.g. PMIDs: 11207361, 16254002, 17937437). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV001832519 SCV002075581 likely pathogenic Metaphyseal chondrodysplasia, McKusick type 2020-10-07 no assertion criteria provided clinical testing

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