ClinVar Miner

Submissions for variant NR_003051.3(RMRP):n.219A>G

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000703896 SCV000832822 pathogenic Anauxetic dysplasia 2018-02-01 criteria provided, single submitter clinical testing 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. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed on the opposite chromosome (in trans) from likely pathogenic variants in several individuals affected with cartilage-hair hypoplasia (PMID:14608646, 15780958, 16832578). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as c.218A>G in the literature. Experimental studies have shown that this sequence change results in reduced expression and increased instability of the gene product (PMID: 17937437). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781820 SCV000920159 pathogenic Metaphyseal chondrodysplasia, McKusick type 2018-12-08 criteria provided, single submitter clinical testing Variant summary: RMRP n.219A>G (also known as 218A>G) involves the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 8e-06 in 125112 control chromosomes (gnomAD and publications). The variant, n.219A>G, has been reported in the literature in individuals affected with Cartilage-Hair Hypoplasia (Nakashima_2003, Harada_2005). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence showing a 10%-<30% decrease in RNA levels associated with this variant (Nakashima_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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