Submissions for variant NR_003051.3(RMRP):n.-22_-14dup

gnomAD frequency: 0.00001  dbSNP: rs1563908167

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000801901	SCV000941700	pathogenic	Anauxetic dysplasia	2024-01-07	criteria provided, single submitter	clinical testing	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 (no rsID available, gnomAD 0.005%). This variant has been observed in individuals with cartilage-hair hypoplasia (PMID: 16244706). 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: 647397). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251401	SCV001426988	likely pathogenic	Metaphyseal chondrodysplasia, McKusick type	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: RMRP n.-22_-14dupTACTCTGTG is located in the untranscribed region upstream of the RMRP coding sequence, and involves the duplication of 9 nucleotides in the promoter region, 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 allele was found at a frequency of 8e-06 in 124400 control chromosomes (gnomAD). The variant, n.-22_-14dupTACTCTGTG, has been reported in the literature in a compound heterozygous individual affected with Cartilage-Hair Hypoplasia (Bonafe_2005). To our knowledge, no experimental evidence demonstrating an impact on protein 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). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002477836	SCV002775443	likely pathogenic	Anauxetic dysplasia 1; Metaphyseal chondrodysplasia, McKusick type; Metaphyseal dysplasia without hypotrichosis	2021-07-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001251401	SCV002075603	likely pathogenic	Metaphyseal chondrodysplasia, McKusick type	2021-03-23	no assertion criteria provided	clinical testing