Submissions for variant NM_000022.4(ADA):c.446G>A (p.Arg149Gln)

gnomAD frequency: 0.00006  dbSNP: rs121908737

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000059104	SCV004102823	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-11-14	reviewed by expert panel	curation	The NM_000022.4(ADA):c.446G>A (p.Arg149Gln) variant in ADA is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 149 (p.Arg149Gln). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 2/107374 observed alleles) is 0.000003610 on gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.0001742). However, we can not use this evidence because it has a filter warning (RF). Expressed ADA activity in Escherichia coli strain SO3834 (ADA-deleted) showed 13.0 +- 13.1% of Wild Type ADA activity, belonging to group IV (range: 4.8–28.2). These results indicate that this variant does not impact the protein function (PMID: 9758612, BS3_moderate). At least one additional missense variant was observed as LP according to SCID VCEP specifications version (PM5_supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS3_Supporting, and PM5_Suppoting. (VCEP specifications version 1).
Counsyl	RCV000059104	SCV000788525	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2017-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307352	SCV002600477	uncertain significance	not specified	2022-10-13	criteria provided, single submitter	clinical testing	Variant summary: ADA c.446G>A (p.Arg149Gln) results in a conservative amino acid change located in the Adenosine deaminase domain (IPR001365) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-06 in 210646 control chromosomes. c.446G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with partial Adenosine Deaminase deficient Severe Combined Immunodeficiency (example, Hirschhorn_1990). However, this variant, reported under the legacy name p.Arg142Gln has also been reported in compound heterozygosity with a null allele in a reportedly unaffected father of an affected proband who was homozygous for the null allele (example, Santisteban_1995). These data do not allow any conclusion about variant significance. At least two publications report conflicting experimental evidence evaluating an impact on protein function (example, Arredondo-Vega_1998, Santisteban_1995). The in-vitro study reporting ADA activity expressed in an EColi cell line reports approximately 13% of normal activity while the Paternal T-cells from the unaffected compound heterozygous individual mentioned above had 40% of normal activity (Arredondo-Vega_1998). The red blood cells (RBC) taken from this unaffected father demonstrated 18% of normal ADA activity with the authors concluding that the residual activity in nucleated T-cells is sufficient to prevent ADA substrate-induced lymphotoxicity and immune dysfunction. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic for a phenotype of partial-ADA deficiency that is dependent upon the overall genotype associated with this variant.
Invitae	RCV000059104	SCV003280426	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-02-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 149 of the ADA protein (p.Arg149Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with partial ADA deficiency (PMID: 2166947). ClinVar contains an entry for this variant (Variation ID: 1963). 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 expected to disrupt ADA protein function. Experimental studies have shown that this missense change affects ADA function (PMID: 9758612, 11067872). This variant disrupts the p.Arg149 amino acid residue in ADA. Other variant(s) that disrupt this residue have been observed in individuals with ADA-related conditions (PMID: 10200056), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM	RCV000002040	SCV000022198	pathogenic	Partial adenosine deaminase deficiency	1990-08-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059104	SCV000090628	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