Submissions for variant NR_003051.4(RMRP):n.129G>C

gnomAD frequency: 0.00319  dbSNP: rs74810894

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535218	SCV000640107	likely benign	Anauxetic dysplasia	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001726225	SCV001962177	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	RMRP: BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824821	SCV002074459	likely benign	not specified	2022-01-28	criteria provided, single submitter	clinical testing	Variant summary: RMRP n.128G>C alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 0.0026 in 130502 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in RMRP causing Cartilage-Hair Hypoplasia (0.0026 vs 0.0072), allowing no conclusion about variant significance. n.128G>C has been reported in the literature in two homozygous individuals affected with primary immunodeficiency (Yu_2016, Platt_2021) but it has also been reported as homozygous occurrence in one control individual in gnomAD v3.1.2. Furthermore, the variant has been observed in another control individual in proven compound heterozygosity with a known pathogenic variant (n.71A>G) (Bonafe_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign for Cartilage-Hair Hypoplasia.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002060322	SCV002495928	uncertain significance	Anauxetic dysplasia 1; Metaphyseal chondrodysplasia, McKusick type; Metaphyseal dysplasia without hypotrichosis	2021-06-14	criteria provided, single submitter	clinical testing	RMRP NR_003051.3 exon 1 n.128G>C: This variant has not been reported in the literature but is present in 0.5% (223/41466) of African alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-35657891-C-G?dataset=gnomad_r3).This variant is present in ClinVar (Variation ID:465201). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV003409793	SCV004109740	uncertain significance	RMRP-related disorder	2023-08-23	criteria provided, single submitter	clinical testing	The RMRP n.128G>C is a noncoding alteration. This variant was reported in the homozygous state in at least one individual with primary immunodeficiency, who also carried a homozygous n.*2T>C variant in the RMRP gene (Yu et al. 2016. PubMed ID: 27484032; reported as g.35657888 in Table S2, Platt et al 2020. PubMed ID: 32888943) and found in one individual undergoing carrier testing (Abulí et al. 2016. PubMed ID: 26990548). This variant is reported in 0.81% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-35657888-C-G). In ClinVar, this variant is interpreted as likely benign/uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/465201/). Although we suspect this variant could be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV001271383	SCV001452494	likely benign	Metaphyseal chondrodysplasia, McKusick type	2020-01-08	no assertion criteria provided	clinical testing