Submissions for variant NM_000022.4(ADA):c.445C>T (p.Arg149Trp)

gnomAD frequency: 0.00001  dbSNP: rs121908733

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000059103	SCV004098708	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-10-10	reviewed by expert panel	curation	The NM_000022.4:c.445C>T (p.Arg149Trp) variant in ADA is a missense variant predicted to cause substitution of arginine by tryptophan at amino acid 149 (p.Arg149Trp). This variant has been reported in an individual with severe combined immunodeficiency and elevated pre-treatment erythrocyte dAXP (2pts, PMID: 10200056) (PP4_Moderate). In experimental studies, the activity of this variant was reported as being 0.012% of wild-type activity (PMID: 9758612) (PS3_Moderate). The highest subpopulation allele frequency 0.00009294 (2/21520) in African/African American population, which is lower than the ADA cutoff gnomAD popmax filtering allele frequency <0.0001742). So PM2 is met. In summary, this variant meets the criteria to be classified as likely pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PP4_Moderate, PS3_Moderate (SCID VCEP specifications version 1.0).
Counsyl	RCV000059103	SCV000790212	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2017-03-23	criteria provided, single submitter	clinical testing
Invitae	RCV000059103	SCV003516355	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-03-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 149 of the ADA protein (p.Arg149Trp). 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 severe combined immunodeficiency (PMID: 10200056, 32888943). ClinVar contains an entry for this variant (Variation ID: 68264). 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). 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: 2166947), 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.
Baylor Genetics	RCV000059103	SCV004213312	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-07-30	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059103	SCV000090627	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