Variant: NR_003051.4(RMRP):n.256_265delCTCAGCGCGG

CA587570153

465208 (ClinVar)

Gene: N/A

Condition: cartilage-hair hypoplasia

Inheritance Mode: Autosomal recessive inheritance

UUID: b488cc54-438b-48e8-bda5-58bd35568af1

Approved on: 2025-06-03

Published on: 2025-06-03

HGVS expressions

NR_003051.4:n.256_265delCTCAGCGCGG
NR_003051.4(RMRP):n.256_265delCTCAGCGCGG
NC_000009.12:g.35657755_35657764del
CM000671.2:g.35657755_35657764del
NC_000009.11:g.35657752_35657761del
CM000671.1:g.35657752_35657761del
NC_000009.10:g.35647752_35647761del
NG_017041.1:g.5257_5266del
NG_033120.1:g.4466_4475del
NR_003051.3:n.257_266del

Likely Pathogenic

• Met criteria codes: PP4_Moderate PM3_Strong

• Not Met criteria codes: BS2 BS1 PS3 PM1 PM2 BA1 PP3

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 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NC_000009.12:g.35657755_35657764del variant is a 10 base pair deletion in RMRP (a non-coding gene). On transcript NR_003051.4 this variant is known as n.256_265delCTCAGCGCGG or n.258_267delCAGCGCGGCT (depending on left vs right shuffling). On transcript NR_003051.3 the variant is known as n.255_264delCTCAGCGCGG or n.257_266delCAGCGCGGCT (depending on left vs right shuffling). The variant may also be referred to as g.254_263delCTCAGCGCGG in the literature. The overall minor allele frequency (MAF) of this variant in gnomAD v4.1.0 is 0.00007166 (49/683800 alleles) and the highest subpopulation MAF (in Admixed American subpopulation) is 0.0008724 (43/49292 alleles). This exceeds the SCID VCEP's criteria for PM2 (<0.0000447) but does not exceed the criteria for BS1 (> 0.00089), therefore no population criteria code is met. Of note, although PM2 is not met, the highest population frequency in gnomAD is the Admixed American subpopulation and all affected individuals identified in the literature are likely from this same subpopulation. This variant has been identified in the literature in 3 unrelated female probands, all of Hispanic or Spanish/Mexican descent, affected with cartilage hair hypoplasia or anauxetic dysplasia (PMID: 17701897, 16838329). All 3 probands have metaphyseal dysplasia (1.0 point) meeting PP4 criteria. In addition to metaphyseal dysplasia, proband P9 in PMID: 16838329 also has hypotrichosis (0.5 point) (1.5 points total, meeting PP4 criteria) and proband P20 also has hypotrichosis (0.5 point), Hirschsprung disease (0.25 point), and T cell lymphopenia (0.5 point) (2.25 points total, meeting PP4_Moderate criteria). All 3 probands have a co-occurring second variant in RMRP. For proband P9 (PMID: 16838329), the co-occurring variant is 116A>G (NR_003051.3:n.117A>G) which has not yet been classified by the SCID VCEP and phase is unknown (0 point for PM3). For proband P20 (PMID: 16838329), the co-occurring variant is 195C>T (NR_003051.3:n.196C>T) which is classified as Pathogenic by the SCID VCEP, however, phase is unknown (0.5 point for PM3). For the proband in PMID: 17701897, the co-occurring variant is 195C>T (NR_003051.3:n.196C>T) which is classified as Pathogenic by the SCID VCEP, and the variants were confirmed in trans via parental testing (1 point for PM3). In addition to these 3 probands identified in the literature, this variant has also been observed in a male proband (of Hispanic descent) with a co-occurring RMRP variant in trans (SCV000640115.6) and indication of disproportionate short stature. The co-occurring variant is n.196C>T which is classified Pathogenic by the SCID VCEP and the variants are confirmed in trans (1 point for PM3). PMID: 17701897 additionally reports that sequencing of the RMRP RT-PCR product of patient with this variant showed absence of detectable levels of the mutation allele. The authors assert this variant is likely a null allele and therefore did not do further analysis for this variant in functional assays. This data does not qualify for PS3 under the SCID VCEP specifications for RMRP. In summary, this variant is classified as Likely Pathogenic based on the following ACMG codes PP4_Moderate (2.25 points), PM3_strong (2.5 points) (SCID VCEP RMRP specifications pilot v1).

Met criteria codes

• PP4_Moderate: 3 patients, all Hispanic and/or Spanish/Mexican ancestry. All are unrelated. 1 proband in PMID: 17701897: metaphyseal dysplasia 1 point, meets PP4 regular strength. 2 probands in PMID: 16838329: P9 with metaphyseal dysplasia (1 point) + hypotrichosis (0.5 point) = 1.5 points, meets PP4 regular strength. P20 with metaphyseal dysplasia (1 point) + hypotrichosis (0.5 point) + Hirschsprung disease (0.25 point) + T lymphopenia (0.5 point) = 2.25 points, meets PP4 moderate strength.
• PM3_Strong: 3 female probands in literature with co-occurring variants. All meet PP4. All are unrelated. 2 additional male probands from Invitae with co-occurring variants. PM3 is met at regular strength using literature probands only but we get to PM3_strong if we also include the Invitae probands. Point breakdown is as follows: PMID: 16838329 female proband: 1 co-occurrence with 116A>G (n.117A>G) (not classified by VCEP, likely VUS at this time since only 1 proband reported (PMID: 16838329) phase unknown. 0 points PMID: 16838329: female proband: 1 co-occurrence with 195C>T (NR_003051.3:n.196C>T, which is classified pathogenic by VCEP), phase unknown. 0.5 point PMID: 17701897: female proband: 1 co-occurrence with 195C>T (NR_003051.3:n.196C>T, which is classified pathogenic by VCEP), confirmed in trans via parental testing. 1 point. Invitae P1: male proband: 1 co-occurrence with n.196C>T (classified pathogenic by VCEP), confirmed in trans. 1 point. Invitae P2: male proband: 1 co-occurrence with n.117A>G (not classified by VCEP, probably VUS), confirmed in trans. Would be 0.25 point IF VCEP classified as VUS, but since not yet classified, 0 point awarded (adding 0.25 point at this time would not upgrade PM3 anyway) Literature probands only: 1.5 points total = PM3 at regular strength Literature + Invitae proband P1: 2.5 points total = PM3_strong

Not Met criteria codes

• BS2: There are no homozygotes in gnomAD
• BS1: Cutoff set by VCEP is MAF > 0.00089. In gnomAD v4.1.0, the overall MAF 0.00007166 (49/683800 alleles) is well below this. The highest subpopulation MAF (Admixed American) is 0.0008724 (43/49292) which is close to but does not exceed the cutoff (OF NOTE: all reported CHH/AD patients in the literature are reported Hispanic or Spanish/Mexican). Therefore BS1 is not met. There are no homozygotes in gnomAD. https://gnomad.broadinstitute.org/variant/9-35657752-CAGCCGCGCTG-C?dataset=gnomad_r4
• PS3: Functional assays allowed per VCEP specification include animal models, endonucleolytic cleavage activity assay, and luciferase reporter assay. Our variant was not tested by any of these assays. PMID: 17701897 does report this variant (referred to as g.254_263delCTCAGCGCGG) and state that sequencing of the RMRP RT-PCR product of patient with this variant showed absence of detectable levels of the mutation allele g.254_263delCTCAGCGCGG (whereas the co-occurring g.195C>T allele was present (data not shown)). Per authors this variant is likely to result in an unstable RNA and therefore represent null allele. Hence, the mutation g.254_263delCTCAGCGCGG was NOT analyzed in the functional assays. Nothing in VCEP specifications allows for using absence via RT-PCR as PS3 and PVS1 is n/a for this gene. So we have no functional assays that qualify for PS3.
• PM1: As per VCEP specifications, PM1 only applies to promoter variants. Our variant is not located in promoter region
• PM2: Cutoff set by VCEP is MAF <0.0000447. In gnomAD v4.1.0 neither the overall MAF 0.00007166 (49/683800 alleles) nor the highest subpopulation MAF (Admixed American) 0.0008724 (43/49292) meets this cutoff (OF NOTE: all reported CHH/AD patients in the literature are reported Hispanic or Spanish/Mexican). Therefore PM2 is not met. There are no homozygotes in gnomAD. https://gnomad.broadinstitute.org/variant/9-35657752-CAGCCGCGCTG-C?dataset=gnomad_r4
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: does not apply - per VCEP specifications PP3 can be applied only for single nucleotide polymorphisms. This variant is a 10bp deletion.