Submissions for variant NR_003051.4(RMRP):n.-18_-2dup

dbSNP: rs727502778

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000015282	SCV000918156	pathogenic	Metaphyseal chondrodysplasia, McKusick type	2018-02-01	criteria provided, single submitter	clinical testing	Variant summary: RMRP n.-19_-3dup17 (also known as r.-19_-3dup17) variant involves the duplication of 17 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 3.3e-05 in 153424 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (3.3e-05 vs 0.0072), allowing no conclusion about variant significance. n.-19_-3dup17 has been reported in the literature in at least two individuals affected with Cartilage-Hair Hypoplasia in compound heterozygous state (Ridanpaa_2001, Bonafa_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, variant n.-20_-19insTCTGTGAAGCTGGGGAC (rs727502779) that resembles to our variant of interest with one nucleotide difference (the 13th nt) has been reported in CHH patient and the expression analysis revealed that the allele with this insertion mutation in the promoter region silenced the gene (Nakashima_RMRP_AJMG_2003). One reputable database, OMIM, submitted clinical-significance assessments for this variant to ClinVar and classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248044	SCV001421505	pathogenic	Anauxetic dysplasia	2024-11-06	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 (rs727502778, gnomAD 0.009%). This variant has been observed in individuals with cartilage-hair hypoplasia (PMID: 11207361). 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). This variant is also known as dupTCTGTGAAGCTGAGGAC at -3. ClinVar contains an entry for this variant (Variation ID: 14214). 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.
Fulgent Genetics, Fulgent Genetics	RCV002482870	SCV002793907	pathogenic	Anauxetic dysplasia 1; Metaphyseal chondrodysplasia, McKusick type; Metaphyseal dysplasia without hypotrichosis	2022-04-19	criteria provided, single submitter	clinical testing
GeneDx	RCV003156213	SCV003845620	pathogenic	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant leads to a loss of RMRP expression (Nakashima et al., 2003); Duplication variants in the promoter region disrupt RNA folding/structure; Also known as r.-20_-4dup17; This variant is associated with the following publications: (PMID: 33726816, 11207361, 14608646)
Laboratorio de Biologia Molecular/Medicina Genomica - IFF/Fiocruz, Instituto Fernandes Figueira, Fundacao Oswaldo Cruz	RCV000015282	SCV004814078	pathogenic	Metaphyseal chondrodysplasia, McKusick type	2024-01-25	criteria provided, single submitter	clinical testing	The variant n.-18_-2dupTCTGTGAAGCTGAGGAC was identified in a compound heterozygous state with another variant in the transcribed region of RMRP gene in an individual affected with Cartilage-Hair Hypoplasia. This alteration is located within the promoter region of the RMRP gene, which encodes an untranslated RNA. Segregation analysis showed that each of the unaffected parents was heterozygous for one of the two variants. Other insertions and duplications in this region have been reported in individuals affected with cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders (PMID: 11207361, 21956908, 21396580). This variant involves the duplication of 17 nucleotides between the TATA box and the transcription initiation site and functional studies have shown that this type of alteration result in reduced expression of the RMRP gene (PMIDs: 11207361, 16254002). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000015282	SCV000035541	pathogenic	Metaphyseal chondrodysplasia, McKusick type	2001-01-26	no assertion criteria provided	literature only