ClinVar Genomic variation as it relates to human health

Variant summary: RMRP n.-24_-12dup13 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 2.1e-05 in 239252 control chromosomes (gnomAD v2.1 and v3.1 datasets). The variant, n.-24_-12dup13, has been reported in the literature in a compound heterozygous patient affected with Omenn syndrome (Kavadas_2008). To our knowledge, no experimental evidence demonstrating an impact on RNA function has 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) and have been demonstrated through functional studies to lead to reduced RMRP transcription (e.g. PMIDs: 11207361, 16254002, 17937437). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

The RMRP n.-24_-12dup13 variant is predicted to result in an in-frame duplication (Non-Coding). This variant was reported in an individual with cartilage-hair hypoplasia (reported as g.-26_-14dup in McCann et al. 2013. PubMed ID: 24217815). Other insertions and duplications immediately upstream of the RMRP coding sequence have been reported in individuals with cartilage-hair hypoplasia (Kavadas et al. 2008. PubMed ID: 18804272; Thiel et al. 2011. PubMed ID: 21396580; Ridanpää et al. 2001. PubMed ID: 11207361; Bonafé et al. 2005. PubMed ID: 16244706). This variant has interpretations of pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/465207/) and has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (rs781730798, gnomAD 0.01%). 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). ClinVar contains an entry for this variant (Variation ID: 551654). 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). For these reasons, this variant has been classified as Pathogenic.