ClinVar Miner

Submissions for variant NR_003051.3(RMRP):n.-24_-12dup (rs781730798)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666774 SCV000791127 likely pathogenic Metaphyseal chondrodysplasia, McKusick type 2017-05-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000666774 SCV000920154 likely pathogenic Metaphyseal chondrodysplasia, McKusick type 2018-08-23 criteria provided, single submitter clinical testing Variant summary: RMRP n.-24_-12dup13 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 allele was found at a frequency of 2.5e-05 in 120992 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. n.-24_-12dup13 has been has been reported in one patient with Omenn sydrome in compound heteterozygous state (*5T>C in trans, Kavadas_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. 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). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000804998 SCV000944939 likely pathogenic Anauxetic dysplasia 2018-12-20 criteria provided, single submitter clinical testing This variant occurs in a non-coding region of the RMRP gene. It does not change the encoded amino acid sequence of the RMRP protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. 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 similar insertions and duplications immediately upstream of the coding sequence have been reported in individuals affected with cartilage-hair hypoplasia (PMID: 21063072, 4608646, 12107819, 16244706, 16832578) . 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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