ClinVar Genomic variation as it relates to human health

DNA sequence analysis of the ADA gene demonstrated a 5 base pair deletion in exon 10, c.956_960del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 2 amino acids downstream of the mutation, p.Glu319Glyfs*3. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ADA protein with potentially abnormal function. The p.Glu319Glyfs*3 change has been reported in the gnomAD database with a frequency of 0.023% in the European sub-population (dbSNP rs912804754). This pathogenic sequence change has previously been described in the homozygous or compound heterozygous state in patients with ADA-related severe combined immunodeficiency (SCID) (PMIDs: 26255240, 8401541, 29744787).

This sequence change creates a premature translational stop signal (p.Glu319Glyfs*3) in the ADA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). This variant is present in population databases (rs771266745, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (PMID: 8401541, 27484032). This variant is also known as del nt1050-54. ClinVar contains an entry for this variant (Variation ID: 193544). For these reasons, this variant has been classified as Pathogenic.

ADA: PVS1, PM2, PP4

Variant summary: The ADA c.956_960delAAGAG (p.Glu319Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent ADA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 16/121412 control chromosomes at a frequency of 0.0001318, which does not exceed the estimated maximal expected allele frequency of a pathogenic ADA variant (0.001633). This variant has been reported in multiple SCID patients in homozgyous or compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23260757, 29744787, 32888943, 26022996, 23280131, 8401541, 27484032, 8227344, 28487086, 8242080, 31858364, 32307643, 27129325, 31589614, 26255240)

This heterozygous p.Glu319GlyfsTer3 variant in ADA was identified by our study in an individual with severe combined immunodeficiency due to adenosine deaminase deficiency in the compound heterozygous state along with a likely pathogenic structural variant. The variant has been reported in at least 9 individuals with severe combined immunodeficiency due to adenosine deaminase deficiency ( PMID: 26376800, 23260757, 26255240) and with 0.02% (30/129198) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs771266745). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. The variant has also been reported in ClinVar as pathogenic by Integrated Genetics/Laboratory Corporation of America, EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, and GeneDx and as likely pathogenic by Counsyl (Variation ID#: 193544). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 319 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ADA gene is an established disease mechanism in autosomal recessive severe combined immunodeficiency. The presence of this variant in at least 2 affected homozygotes and in combination with a likely pathogenic variant, and in 3 individuals with severe combined immunodeficiency increases the likelihood that p.Glu319GlyfsTer3 is pathogenic (PMID:26376800). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive severe combined immunodeficiency. ACMG/AMP Criteria applied: PVS1, PM3_strong (Richards 2015).