Submissions for variant NM_000022.4(ADA):c.646G>A (p.Gly216Arg)

gnomAD frequency: 0.00006  dbSNP: rs121908723

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000002045	SCV004242245	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-01-24	reviewed by expert panel	curation	NM_000022.4 :c.646G>A is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 216 (p.Gly216Arg). The filtering allele frequency (the upper threshold of the 95% CI of 46/1180026) of the c.646G>A variant in ADA is 0.00002743 for European Non-Finnish chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.0001742) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).The variant has been reported to segregate with SCID in 4 affected family members from 2 families (PP1_strong; PMID : 26255240). This variant has been detected in 15 individuals with ADA deficient SCID. Of those individuals, 3 were compound heterozygous for the variant and a pathogenic variant (Glu319Glyfs*320 ,confirmed in trans ,1pt.). 12 individuals were homozygous for the variant (1 pt.) (total: 2 pts; PM3_Strong ,PMID : 26255240). Male patient with SCID (0.5 pt.), genome sequencing conducted (0.5 pt.), reduced ADA enzyme activity in patient cells (1 pt),SCID phenotype corrected by exogenous ADA supplementation (1 pt.),Increased dATP in pretreatment erythrocytes (2 pts.). (PP4_Moderate (5 pts.), PMID: 1680289). ADA activity in SØ3834 was 30.4 nmol/h/mg protein which is .012 % of wild type ADA activity indicating that this variant impacts protein function (PMID : 9758612, PS3_Moderate). Based on the above evidence, the variant may be classified as pathogenic 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_strong,PM2_supporting,PM3_strong,PP4_moderate,PS3_moderate (VCEP specifications version 1).
GeneDx	RCV000256171	SCV000321380	pathogenic	not provided	2017-07-10	criteria provided, single submitter	clinical testing	The G216R missense variant in the ADA gene has been reported previously in association with adenosine adeaminase deficiency in patients of varied ancestries (Hirschhorn et al., 1991; Arredondo-Vega et al., 1998; Adams et al., 2015; Baffelli et al., 2015). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G216R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R211H/C, V213F, A215T, E217K) have been reported in the Human Gene Mutation Database in association with ADA-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In addition, functional studies have shown that the G216R variant results in reduced catalytic activity and early clinical presentation of the disorder (Arredondo-Vega et al., 1998). Therefore, we consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000002045	SCV000693973	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2017-08-27	criteria provided, single submitter	clinical testing	Variant summary: The c.646G>A (p.Gly216Arg) in ADA gene is a missense change that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the active site of conserved domain and mutations were proven to lead to severe SCID presentation due to complete abolishment of all residual enzyme activity. The variant is present in the large control population dataset of ExAC at a frequency 1.65e-05 (2/121232 chrs tested). The variant has been identified homozygously or in the compound heterozygous state in numerous affected individuals with severe presentation. Lastly, multiple reputable databases/diagnostic centers classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Counsyl	RCV000002045	SCV000789553	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2017-02-14	criteria provided, single submitter	clinical testing
Invitae	RCV000002045	SCV000952135	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 216 of the ADA protein (p.Gly216Arg). This variant is present in population databases (rs121908723, gnomAD 0.004%). This missense change has been observed in individual(s) with adenosine deaminase deficiency (PMID: 1346349, 1680289, 9108404, 9758612, 26255240). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1968). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ADA function (PMID: 8258146, 9108404, 9758612). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000002045	SCV001522472	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2019-09-29	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000002045	SCV001977503	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-08-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000002045	SCV002021883	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2019-11-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000256171	SCV004704419	pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ADA: PM3:Very Strong, PM2, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV003904795	SCV004724875	pathogenic	ADA-related condition	2024-02-29	criteria provided, single submitter	clinical testing	The ADA c.646G>A variant is predicted to result in the amino acid substitution p.Gly216Arg. This variant in the homozygous and compound heterozygous conditions was reported in multiple individuals with adenosine deaminase deficiency/severe combined immunodeficiency (see example: Hirschhorn et al 1991. PubMed ID: 1680289; Mantravadi et al. 2021. PubMed ID: 3453967; Pajno et al. 2020. PubMed ID: 32307643; Verhagen et al. 2020. PubMed ID: 31858364). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.
OMIM	RCV000002045	SCV000022203	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	1991-10-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000002045	SCV000090639	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
Natera, Inc.	RCV000002045	SCV001460809	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2020-09-16	no assertion criteria provided	clinical testing