Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000059115 | SCV001413001 | pathogenic | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | 2024-10-28 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 297 of the ADA protein (p.Pro297Gln). This variant is present in population databases (rs121908718, gnomAD 0.02%). This missense change has been observed in individual(s) with partial adenosine deaminase (ADA) deficiency (PMID: 2166947, 2783588). ClinVar contains an entry for this variant (Variation ID: 1961). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ADA protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ADA function (PMID: 2166947). This variant disrupts the p.Pro297 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). 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. |
Mayo Clinic Laboratories, |
RCV002260959 | SCV002541684 | uncertain significance | not provided | 2021-09-01 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV002307351 | SCV002600454 | uncertain significance | not specified | 2022-10-12 | criteria provided, single submitter | clinical testing | Variant summary: ADA c.890C>A (p.Pro297Gln) 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 2.8e-05 in 251492 control chromosomes (gnomAD). c.890C>A has been reported in the literature in the homozygous and compound heterozygous states in two partially ADA deficient children, identified through Newborn Screening (Hirschhorn_1989, Hirschhorn_1990). A later report by the same authors (Hirschhorn_1995) stated that up to that date, the children had not presented with immunodeficiency. GeneReviews defines partial ADA deficiency as a benign condition which is compatible with normal immune function (PMID 20301656). These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. Experimental evidence evaluating an impact on protein function demonstrated the variant to have normal electrophoretic mobility and abnormal heat stability, with ADA activity measured at 56% in homozygous lymphoid cells (Hirschhorn_1989, Hirschhorn_1990). A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic, while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Gene |
RCV002260959 | SCV003930939 | pathogenic | not provided | 2023-05-09 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as transfection of the mutant cDNA into heterologous cells resulted in expression of a heat-labile ADA of normal electrophoretic mobility, properties exhibited by the ADA in the patients' cells (Hirschhorn et al., 1989); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9225964, 2783588, 21898656, 24772956, 20493397, 2166947, 31589614, 34975878, 23645737) |
Baylor Genetics | RCV000059115 | SCV004216604 | likely pathogenic | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | 2024-03-25 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000002038 | SCV000022196 | pathogenic | Partial adenosine deaminase deficiency | 1989-02-01 | no assertion criteria provided | literature only | |
Uni |
RCV000059115 | SCV000090643 | not provided | Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency | no assertion provided | not provided | ||
Prevention |
RCV004752679 | SCV005345691 | likely pathogenic | ADA-related disorder | 2024-09-04 | no assertion criteria provided | clinical testing | The ADA c.890C>A variant is predicted to result in the amino acid substitution p.Pro297Gln. This variant has been reported in the homozygous and compound heterozygous states in individuals with partial adenosine deaminase (ADA) deficiency (Hirschhorn et al. 1989. PubMed ID: 2783588; Hirschhorn et al. 1990. PubMed ID: 2166947). Functional studies suggest that this variant impacts ADA function (Hirschhorn et al. 1989. PubMed ID: 2783588; Hirschhorn et al. 1990. PubMed ID: 2166947). Of note, another variant impacting the same amino acid [c.890C>T (p.Pro297Leu)] was reported in the compound heterozygous state in an individual with predominantly antibody deficiency (Patient P221, Rojas-Restrepo. 2021. PubMed ID: 34975878). The c.890C>A (p.Pro297Gln) variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar regarding its pathogenicity, ranging from pathogenic to likely pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/1961/). Taken together, this variant is interpreted as likely pathogenic. |