Submissions for variant NM_000022.4(ADA):c.425G>A (p.Arg142Gln)

gnomAD frequency: 0.00399  dbSNP: rs61732239

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000059101	SCV004242242	benign	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-01-10	reviewed by expert panel	curation	NM_000022.4(ADA):c.425G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 142 (p.Arg142Gln). The filtering allele frequency (the upper threshold of the 95% CI of 975/74574 alleles) of the c.425G>A variant in ADA is 0.01222 for African/African American chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00721) for BA1 and therefore meets this criterion (BA1). This variant has been observed in 6 homozygous individuals in gnomAD v.4, a condition with full penetrance at an early age (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1).
GeneDx	RCV000523342	SCV000617081	uncertain significance	not provided	2018-04-23	criteria provided, single submitter	clinical testing	The R142Q variant in the ADA gene has been reported previously, along with another variant, in the unaffected father of a Somali child with SCID who was homozygous for a nonsense variant in the ADA gene (Santisteban et al., 1995). The R142Q variant is observed in 265/19952 (1.3%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016). The R142Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In vitro function studies showed the R142Q variant reduced ADA enzyme activity between 42.8-80% compared to wild type (Richard et al., 2002; Santisteban et al., 1995). We interpret R142Q as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000059101	SCV000644842	likely benign	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-01-26	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000059101	SCV000898504	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-03-30	criteria provided, single submitter	clinical testing	ADA NM_000022.3 exon 5 p.Arg142Gln (c.425G>A): This variant has been reported in the literature in one individual, the unaffected father of a proband with Severe Combined Immunodeficiency (SCID). This variant was not identified in the affected proband, and this proband was reported to carry a different homozygous nonsense mutation (Santisteban 1995 PMID:8589684). This variant is present in 1.3% (276/20894) of African alleles including 2 homozygotes in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/20-43254263-C-T). This variant is present in ClinVar (Variation ID: 68262). This variant amino acid Glutamine (Gln) is present in 9 species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. Functional studies suggest a reduction in ADA activity vs. wild type with literature suggesting this may be a "partial" variant; however, these studies may not accurately represent in vivo biological function (Santisteban 1995 PMID:8589684, Arredondo-Vega 1998 PMID:9758612).In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore, the clinical significance of this variant is uncertain.
Mendelics	RCV000059101	SCV001141237	benign	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000059101	SCV001301102	benign	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Genome-Nilou Lab	RCV000059101	SCV001977371	likely benign	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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222377	SCV002500611	likely benign	not specified	2022-03-03	criteria provided, single submitter	clinical testing	Variant summary: ADA c.425G>A (p.Arg142Gln) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 202328 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in ADA causing Severe Combined Immunodeficiency phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.425G>A has been reported in the literature in an unaffected compound heterozygous (Q3X/R142Q) individual with an affected child who was homozygous for Q3X (Santisteban_1995). Two studies have demonstrated this variant partially reduce enzyme activity in vitro (Santisteban_1995 and Arredono-Vega_1998). Additionally, Richard_2000 demonstrated that recombinant human ADA bearing the R142Q mutation impaired binding to a CD26+ ADA-deficient human T cell line. These reports do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant VUS (n=4), likely benign (n=2) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000523342	SCV004564697	likely benign	not provided	2023-09-11	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059101	SCV000090625	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.	RCV000059101	SCV001455706	likely benign	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2020-01-07	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000523342	SCV001932721	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000523342	SCV001964166	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905030	SCV004724041	likely benign	ADA-related disorder	2019-08-06	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).