ClinVar Miner

Submissions for variant NR_003051.3(RMRP):n.-21_-9dupACTCTGTGAAGCT (rs751921616)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000781816 SCV000920155 likely pathogenic Metaphyseal chondrodysplasia, McKusick type 2018-09-28 criteria provided, single submitter clinical testing Variant summary: RMRP n.-21_-9dup13 variant involves the duplication of 13 nucleotides in the promoter region of RMRP, which is located between the TATA box (-33 to -25) and the transcription initiation site. The variant was absent in 121242 control chromosomes. n.-21_-9dup13 has been reported in the literature in individuals affected with Cartilage-Hair Hypoplasia (Bonafe_2005, Turkkani_2009). Additionally, the variant has been shown to impair chondrogenic trans-differentiation in fibroblasts of an affected patient (Steinbusch_2017) Similar type of duplications have been reported in CHH patients and shown to reduce the transcription of RMRP and were associated with lower shRNA expression (Ridanpaa_2001, PMID 11207361, Hermanns_2005, PMID 16254002). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000526886 SCV000640112 likely pathogenic Anauxetic dysplasia 2017-06-19 criteria provided, single submitter clinical testing This sequence change occurs in the RMRP gene, which encodes the RNA component of the RNase mitochondrial RNA processing (MRP) complex and does not result in a protein product. This variant involves a sequence duplication at -21 to -9 positions of the RMRP promoter inserting 13 nucleotides between -9 and -8 positions of the RMRP promoter. While this variant is present in population databases (rs751921616), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed to co-occur with the RMRP n. 147G>A variant in two individuals affected with RMRP-related disorders (PMID: 16244706, Invitae). This variant is also known as g.22_10dupACTCTGTGAAGCT in the literature. In addition, this variant is located in the promoter region between the TATA box and the transcription initiation site, and other similar insertions and duplications immediately upstream of the coding sequence have been reported in individuals affected with cartilage-hair hypoplasia (PMID: 11207361, 16838329, 17189938, 21570718). Experimental analyses using patient derived cells, as well as in vitro transfection studies, have shown that these promoter insertions result in silencing of RMRP transcription and reduced expression of the gene product (PMID: 11207361, 16254002). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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