ClinVar Genomic variation as it relates to human health

NM_002185.5(IL7R):c.379G>A is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 127 (p.Val127Ile). The highest population minor allele frequency in gnomAD v4 is 0.00002991 (1/33436) in African/African American population which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, meeting this criterion (PM2_Supporting). c.379G>A mutation in IL7R abolishes splicing of exons 3-4 and replaces it with splicing of exons 2-4, which introduces a STOP site resulting in premature termination of IL-7Ra translation (Nonsense mediated decay) (PVS1) PMID: 35418989. Female patient with SCID (0.5 pt.), reduced CD127 expression demonstrated by flow cytometry (1 pt.),T-B+NK+ lymphocyte subset profile (0.25 pt.) Total :1.75 pts. (PP4_met ; PMID: 35418989).The patient (PMID: 35418989) was found homozygous for the mutation (0.5 pt.) (PM3_supporting). In summary, this variant meets the criteria to be classified as a Pathogenic variant for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_supporting,PVS1, PP4_met,PM3_supporting (VCEP specifications version 1).

The homozygous c.379G>A variant that we identified is a novel pathogenic mutation that results in aberrant IL7RA RNA splicing, absent IL-7Ra expression, and defective T cell production and function. The mutated residue is the last nucleotide at the 3' end of exon 3. It was reported in the annotation file of the sequence that it causes the change of a valine to isoleucine at position 127 of the protein (p.V127I). However, our molecular and functional studies showed that the mutated residue affect the splice donor site of intron 3, abolishing splicing of exon 3 to exon 4, replacing it by splicing of exon 2 to exon 4 that resulted in an RNA that lacked exon 3, and the introduction of a STOP signal downstream of cysteine at position 74 (p.C74*) of the protein rather than converting V to I at position 127. This prematurely terminated IL-7Ra translation at p.C74 and abolished IL-7Ra surface expression. Based on these results, we classified the mutation as "pathogenic". The patient was transplanted from an HLA matched donor which resulted in the reconstitution of her immune cells and correction of her disease.