ClinVar Miner

Submissions for variant NR_003051.3(RMRP):n.5C>T (rs772443941)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667744 SCV000792243 pathogenic Metaphyseal chondrodysplasia, McKusick type 2017-06-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000667744 SCV000920160 pathogenic Metaphyseal chondrodysplasia, McKusick type 2018-12-10 criteria provided, single submitter clinical testing Variant summary: The RMRP n.5C>T (also known as n.4C>T) variant was found at a frequency of 0.00012 in 154346 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.00012 vs 0.0072), allowing no conclusion about variant significance. The variant, n.5C>T, has been reported in the literature in multiple individuals affected with Cartilage-Hair Hypoplasia (Bordon_2010, Hermanns_2006, Kavadas_2008, Munoz-Robles_2006, Bonafe_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000799558 SCV000939227 uncertain significance Anauxetic dysplasia 2018-08-23 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 present in population databases (rs772443941), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in individuals with symptoms consistent with the cartilage hair hypoplasia-anauxetic dysplasia spectrum (PMID: 17701897, 12107819). This variant is also referred to as g.4C>T or 4T in the literature. Experimental studies have shown that this sequence change disrupts RMRP activity (PMID: 17701897). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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