Submissions for variant NR_003051.3(RMRP):n.71A>G

gnomAD frequency: 0.00156  dbSNP: rs199476103

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000313899	SCV000329496	pathogenic	not provided	2016-07-01	criteria provided, single submitter	clinical testing	The RMRP gene is not translated and codes for the RNA component of a mitochondrial RNA processing endoribonuclease. The r.(71 a>g) variant has been published previously in association with cartilage-hair hypoplasia (CHH) (Ridanpaa et al., 2001; Kainulainen et al., 2014). The r.(71 a>g) variant is the most common pathogenic variant in the RMRP gene, and in the Finnish population the carrier frequency for this variant has been estimated to be as high as 1 in 76 (Sulisalo et al., 1994). This substitution occurs at a position that is conserved across species. Functional analysis of the r.(71 a>g) variant found that it is associated with reduced cleavage activity and abnormal ribosomal processing (Thiel et al., 2007; Hermanns et al., 2005). Therefore, we consider this variant to be pathogenic.
Invitae	RCV000555900	SCV000640120	pathogenic	Anauxetic dysplasia	2024-01-30	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 (rs199476103, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders (PMID: 16097009, 16838329). It is commonly reported in individuals of Amish ancestry (PMID: 8034306, 12888988). This variant is also known as g.70A>G. ClinVar contains an entry for this variant (Variation ID: 14208). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant is located in a highly conserved P3 domain involved mainly in mRNA cleavage and have been reported to cause impaired cleavage of both 5.8S rRNA and cyclin B2 mRNA in transfected human fibroblast cells (PMID: 10026268, 11207361, 17701897). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763613	SCV000894467	pathogenic	Anauxetic dysplasia 1; Metaphyseal chondrodysplasia, McKusick type; Metaphyseal dysplasia without hypotrichosis	2022-03-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000015275	SCV001194191	pathogenic	Metaphyseal chondrodysplasia, McKusick type	2019-11-18	criteria provided, single submitter	clinical testing	NR_003051.3(RMRP):c.71A>G is classified as pathogenic in the context of cartilage-hair hypoplasia. Sources cited for classification include the following: PMID 16838329, 12107819 and 17701897. Classification of NR_003051.3(RMRP):c.71A>G is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000015275	SCV001362275	pathogenic	Metaphyseal chondrodysplasia, McKusick type	2019-10-18	criteria provided, single submitter	clinical testing	Variant summary: RMRP n.71A>G (noncoding transcript variant; legacy name 70A>G) is a comon pathogenic founder mutation. The variant allele was found at a frequency of 0.00087 in 130486 control chromosomes (gnomAD). This frequency does not exceed the expected maximal pathogenic allele frequency estimated for pathogenic variants in RMRP (0.0072). n.71A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cartilage-Hair Hypoplasia (CHH; e.g. Ridanpaa_2001). These data indicate that the variant is very likely to be associated with disease. n.71A>G has been reported to impair cleavage of both 5.8S rRNA and cyclin B2 mRNA in the literature (e.g. Hermanns_2005, Thiel_2007). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014). All laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Undiagnosed Diseases Network, NIH	RCV000015275	SCV001827222	pathogenic	Metaphyseal chondrodysplasia, McKusick type	2021-06-03	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000313899	SCV001832468	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000313899	SCV002545681	pathogenic	not provided	2022-07-01	criteria provided, single submitter	clinical testing	RMRP: PP1:Strong, PS4, PM1
Institute of Human Genetics, University of Leipzig Medical Center	RCV000015275	SCV003925644	likely pathogenic	Metaphyseal chondrodysplasia, McKusick type	2023-04-14	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NR_003051.3:n.119A>G._x000D_ Criteria applied: PS3, PM3_STR
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000313899	SCV004026161	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000313899	SCV004234213	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003944823	SCV004759410	pathogenic	RMRP-related condition	2023-12-09	criteria provided, single submitter	clinical testing	The RMRP n.71A>G is a noncoding alteration. This variant, also known as n.70A>G in the literature, was reported in the homozygous or compound heterozygous state in numerous individuals with RMRP-associated disorders (Ridanpää et al. 2001. PubMed ID: 11207361; Thiel et al. 2007. PubMed ID: 17701897). Functional studies showed that the n.71A>G substitution results in impaired cleavage activity and aberrant ribosomal processing (Hermanns et al. 2005. PubMed ID: 16254002; Thiel et al. 2007. PubMed ID: 17701897). This variant is reported in 0.87% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
OMIM	RCV000015275	SCV000035534	pathogenic	Metaphyseal chondrodysplasia, McKusick type	2006-10-01	no assertion criteria provided	literature only
OMIM	RCV000015276	SCV000035535	pathogenic	Metaphyseal dysplasia without hypotrichosis	2006-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000015275	SCV000054462	pathologic	Metaphyseal chondrodysplasia, McKusick type	2012-03-15	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Reproductive Health Research and Development, BGI Genomics	RCV000015276	SCV001142395	pathogenic	Metaphyseal dysplasia without hypotrichosis	2020-01-06	no assertion criteria provided	curation	NR_003051.3:n.71A>G in the RMRP gene has an allele frequency of 0.009 in European (Finnish) subpopulation in the gnomAD database. This variant also known as 70A>G in literatures, has been reported in 4/22 Cartilage-Hair Hypoplasia patients in a homozygous state and also in in compound heterozygous constellation with the transversion 262C>G in two sibs and in an unrelated patient and a compound heterozygote of the 70A>G mutant allele and the ( 14_20dup) promoter duplication(PMID: 16838329). This sequence change occurs in the RMRP gene, which encodes the RNA component of the RNase mitochondrial RNA processing (MRP) complex and does not result in a protein product. Functional analysis of the r.(71 a>g) variant found that it is associated with reduced cleavage activity and abnormal ribosomal processing ( PMID: 17701897; 16838329). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3; PP4.
Natera, Inc.	RCV000015275	SCV001457387	pathogenic	Metaphyseal chondrodysplasia, McKusick type	2020-09-16	no assertion criteria provided	clinical testing