Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NR_003051.3(RMRP):n.-22_-13dup10

CA257182

14210 (ClinVar)

Gene: RMRP (HGNC:6023)

Condition: cartilage-hair hypoplasia (MONDO:0009595)

Inheritance Mode: Autosomal recessive inheritance

UUID: 557eeee2-413e-41a4-b13c-f736741c8fa1

Approved on: 2026-02-21

Published on: 2026-02-25

HGVS expressions

NR_003051.3(RMRP):n.-22_-13dup10

NC_000009.12:g.35658031_35658040dup

CM000671.2:g.35658031_35658040dup

NC_000009.11:g.35658028_35658037dup

CM000671.1:g.35658028_35658037dup

NC_000009.10:g.35648028_35648037dup

NG_017041.1:g.4979_4988dup

NG_033120.1:g.4742_4751dup

Pathogenic

PP4_Moderate PM2_Supporting PM3_Strong PM1_Strong PM4

BS4 BS1 BS3 BS2 BP4 BP1 BP3 BP2 BP7 BP5 BA1 PS4 PS2 PS1 PS3 PP3 PP2 PP1 PVS1 PM6 PM5

Evidence Links 0

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RMRP Version 1.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NC_000009.12:g.35658031_35658040dup variant is a 10-base duplication in the promoter region of RMRP. This variant is also described as NR_003051.3(RMRP):n.-22_-13dup10. No population data was found for this allele in gnomAD v4. (PM2_supporting). The duplication lies within the critical promoter region, between the TATA box (n.-32 to n.-24) and the transcription start site (n.4), consistent with functional importance and the variant also meets PM2 per specification caveat. (PM1_strong). The insertion of 6 or more nucleotides increasing the distance between TATA box (n.-32 to n.-24) and the transcription start site (n.4), which has been shown to disrupt promoter function (PM4_Moderate). Klemetti et al., 2017 (PMID: 28094436) describes 4 patients with CHH that were compound heterozygous for g.70A>G and a 10-nt duplication at position −13 (reported sequence TACTCTGTGA). Patient 1 was the index case and Patients 2–4 were identified from the Finnish Skeletal Dysplasia Register. The g.70A>G (NC_000009.12:g.35657948T>C) variant has been previously classified as pathogenic by the SCID VCEP RMRP group. For Patient 1 "Parents were both heterozygous carriers of one of the mutations" confirming phase in trans with pathogenic variant (1pt). Phase is not given for patients 2-4 identified in th registry (0.5ptx 3 = 1.5 pts). (PM3_Strong, total 2.5pts) Clinical data shared through internal communication with Dr. Svetlana Vakkilainen describes a patient with CHH from 263G>T /-22_-13dup (patient 21 from PMID: 38187867). In the communication the patient met the following PP4 criteria: diagnostic criteria for SCID (1pt), SCID genetic testing conducted (0.5 pt), metaphyseal dysplasia (1 pt), and T cell lymphopenia (0.5pts). (PP4_Moderate, total 3 points) In summary, this variant is classified as Pathogenic based on the following ACMG/AMP criteria (SCID VCEP RMRP specifications Version 1.1): PM2 Supporting, PM1_strong, PM4_moderate, PM3_Strong, PP4_Moderate).

PP4_Moderate

Clinical data shared through internal communication with Dr. Svetlana Vakkilainen describes a patient with CHH from 263G>T /-22_-13dup (patient 21 from PMID: 38187867). In the communication the patient met the following PP4 criteria: diagnostic criteria for SCID (1pt), SCID genetic testing conducted (0.5 pt), metaphyseal dysplasia (1 pt), and T cell lymphopenia (0.5pts). (PP4_Moderate, total 3 points)

PM2_Supporting

No population data was found for this allele in gnomAD v4. (PM2_supporting).

PM3_Strong

Klemetti et al., 2017 (PMID: 28094436) describes 4 patients with CHH that were compound heterozygous for g.70A>G and a 10-nt duplication at position −13 (reported sequence TACTCTGTGA). Patient 1 was the index case and Patients 2–4 were identified from the Finnish Skeletal Dysplasia Register. The g.70A>G (NC_000009.12:g.35657948T>C) variant has been previously classified as pathogenic by the SCID VCEP RMRP group. For Patient 1 "Parents were both heterozygous carriers of one of the mutations" confirming phase in trans with pathogenic variant (1pt). Phase is not given for patients 2-4 identified in th registry (0.5ptx 3 = 1.5 pts). (PM3_Strong, total 2.5pts)

PM1_Strong

The duplication lies within the critical promoter region, between the TATA box (n.-32 to n.-24) and the transcription start site (n.4), consistent with functional importance and the variant also meets PM2 per specification caveat. (PM1_strong).

PM4

The insertion of 6 or more nucleotides increasing the distance between TATA box (n.-32 to n.-24) and the transcription start site (n.4), which has been shown to disrupt promoter function (PM4_Moderate).

BS4