Submissions for variant NR_003051.3(RMRP):n.-5delins17

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000531018	SCV000640118	likely pathogenic	Anauxetic dysplasia	2017-07-17	criteria provided, single submitter	clinical testing	This sequence change occurs in the promoter region of the RMRP gene, which encodes an RNA molecule that does not result in a protein product. RMRP is a ribonuclease for mitochondrial RNA processing involved in the processing of pre-rRNA and the generation of RNA primers for mitochondrial DNA replication. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RMRP-related disease. 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: 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.