ClinVar

Description

The c.256_257del (p.Lys86ValfsTer33) variant in RAG1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense-mediated decay. The variant causes a truncation of a functionally important region (removes amino acids 86-1011) of the RAG1 protein. The variants also cause the usage of an alternative in-frame start codon (Met183), but the alternatively transcribed protein has decreased recombination activity and mislocalization in cells (PMIDs 11121059, 27301863). So the variant may cause protein loss-of-function (PVS1; PMIDs 11121059, 27301863). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 6/128846 observed alleles) is 0.000007030 in gnomAD v2.1.1 which is below the SCID-VCEP threshold (<0.000102) and therefore meets this criterion (PM2_Supporting). The in vitro recombination assay shows that the p.Lys86ValfsTer33 variant in RAG1 causes a decrease of recombination activity to below 25%, indicating that the variant impacts the protein function. (PS3_Moderate; PMID 24290284). One homozygous individual with OS. One homozygous individual with SCID. 1pt for PM3. (PMID 11121059, patient OS8; PMID 32655540, patient #32). PM3 met. One patient with this variant was diagnosed with SCID (0.5pt). The patient showed T-B-NK+ lymphocyte profile (0.5pt). 1pt in total, PP4 met. (PMID 32655540, proband #32) In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PM3_moderate, PS3_moderate, and PP4_supporting. (VCEP specifications version 1).