Variant: NR_003051.4(RMRP):n.264G>T

Version: 1.2
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CA257181

14209 (ClinVar)

Gene: RMRP (HGNC:6023)

Condition: cartilage-hair hypoplasia

Inheritance Mode: Autosomal recessive inheritance

UUID: 7fb7723f-2d30-49a6-9690-e58f442e90a9

Approved on: 2025-09-30

Published on: 2025-12-09

HGVS expressions

NR_003051.4:n.264G>T
NR_003051.4(RMRP):n.264G>T
NC_000009.12:g.35657756C>A
CM000671.2:g.35657756C>A
NC_000009.11:g.35657753C>A
CM000671.1:g.35657753C>A
NC_000009.10:g.35647753C>A
NG_017041.1:g.5263G>T
NG_033120.1:g.4467C>A
NR_003051.3:n.263G>T

Pathogenic

• Met criteria codes: PM3_Very Strong PP1 PP4

• Not Met criteria codes: PM2

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

This variant is present in gnomAD v.4 at a Total allele frequency of 0.00003793, which is lower than the PM2_supporting threshold 0.0000447. while in the subgroup Finnish European, the allele frequency is 0.000552 [24/43478], which is higher than the threshold of 0.0000447. Therefore, the PM2_supporting was not met. At least one patient presented Methapyseal dysplasia (+1.0 points) and hypotrichosis (+0.5 points)(1.5 points, PP4, PMID: 11207361). This variant is reported in trans with the variant (70A>g) in 6 independent families (+1.0 points each), reaching a total score of 6.0, and PM3_VeryStrong is met (PMID: 11207361). A multiple-case family with this variant in trans with n.70A>C is reported with two affected siblings, meeting PP1 (PMID: 11207361). In summary, this variant meets the criteria to be classified as Pathogenic for Autosomal recessive Cartilage Hair Hypoplasia based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM3_VeryStrong, PP4, and PP1 (VCEP specifications version 1).

Met criteria codes

• PM3_Very Strong: This variant is reported in trans with the variant (70A>g) in 6 patients (+1.0 points each). The total score is 6 meeting this criterion PM3_VeryStrong. PMID: 11207361
• PP1: A multiple-case family with this variant in trans with n.70A>C is reported with two affected siblings. Therefore this criterion is met at default strength.
• PP4: At least one patient presented Methapyseal dysplasia (+1.0 points) and hypotrichosis (+0.5 points) and therefore this criterion is met at default strength (PMID: 11207361).

Not Met criteria codes

• PM2: This variant is present in gnomAD v.4 at a Total allele frequency of 0.00003793, which is lower than the PM2_supporting threshold 0.0000447. while in the subgroup Finnish European, the allele frequency is 0.000552 [24/43478], which is higher than the threshold of 0.0000447. Therefore, the PM2_supporting was not met. NOTE: gnomAD does not provide GroupMax Filtering AF for this variant, therefore for this curation, we use the total allele frequency.