ClinVar Genomic variation as it relates to human health

NM_000022.4:c.631C>T is a missense variant predicted to cause substitution of Arginine by Cysteine at amino acid 211 (p. Arg211Cys). The highest population minor allele frequency in gnomAD v4 is 0.0005167 (31/60000) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). The variant has been reported to segregate with SCID in 2 affected family members from 1 family (PP1_moderate; PMID :8051429). Patient was found heterozygous for R211C & L107P which is classified as likely pathogenic by SCID VCEP (1 pt.) (PM3) (PMID: 2166947).Another missense variant [c.632G>A, p.Arg211His)] in the same codon has been classified as pathogenic for SCID by the ClinGen SCID VCEP (PM5). In summary, this variant meets the criteria to be classified as a Likely Pathogenic variant for autosomal recessive severe combined immunodeficiency due to ADA deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PP1_moderate,PM3,PM5(VCEP specifications version 1).

The ADA c.631C>T (p.Arg211Cys) variant was first reported by Hirschhorn et al. (1990) in a child with partial adenosine deaminase (ADA) deficiency. This patient was compound heterozygous for p.Arg211Cys and a second missense variant, and had approximately 8% residual ADA activity in lymphoid cells. The p.Arg211Cys variant was subsequently identified in a compound heterozygous state with a second deletion variant in two siblings with ADA deficiency and combined immunodeficiency, with no detectable ADA activity. The p.Arg211Cys variant was also detected in a heterozygous state in the mother, two additional siblings, and in a patient's child, all of whom had normal or below normal ADA activity (Shovlin et al. 1994). Control data are unavailable for this variant, but it is reported at a frequency of 0.00078 in the Latino population of the Exome Aggregation Consortium. Expression studies in COS cells by Jiang et al. (1997) showed that the p.Arg211Cys variant resulted in residual ADA activity of approximately 4% of normal. Another variant at this position, p.Arg211His, has also been seen in patients with ADA deficiency (Akeson et al. 1988; Arredondo-Vega et al. 1998). Based on the collective evidence, the p.Arg211Cys variant is classified as likely pathogenic for adenosine deaminase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Variant summary: ADA c.631C>T (p.Arg211Cys) results in a non-conservative amino acid change located in the adenosine deaminase domain (IPR001365) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251340 control chromosomes, predominantly at a frequency of 0.00069 within the Latino subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in ADA causing Severe Combined Immunodeficiency (0.00013 vs 0.0014), allowing no conclusion about variant significance. c.631C>T has been reported in the literature as a compound heterozygous genotype in an individual with partial ADA deficiency, detected as 8% ADA activity in lymphoid cells, and in two siblings affected with late onset severe combined immunodeficiency with ADA deficiency, where the variant segregated with disease in the family (e.g. Hirschhorn_1990, Shovlin_1994). Multiple publications report evidence evaluating an impact on protein function (e.g. Hirschhorn_1990, Jiang_1997, Arredondo-Vega_1998) and experiments expressing the variant in an in vitro model system found that the variant results in <5% of normal activity. Another variant, p.Arg211His, affecting the same amino acid residue has also been observed in individuals with severe combined immunodeficiency and has been classified as pathogenic (ClinVar ID: 1957). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as either pathogenic (n=1) or likely pathogenic (n=3), and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 211 of the ADA protein (p.Arg211Cys). This variant is present in population databases (rs121908740, gnomAD 0.07%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 2166947, 8051429, 9616253). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1966). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 9361033, 9758612). This variant disrupts the p.Arg211 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1974554, 9414266, 9758612, 26376800). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.