Submissions for variant NM_000022.4(ADA):c.715G>A (p.Gly239Ser)

gnomAD frequency: 0.00003  dbSNP: rs777820729

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000378500	SCV004242246	uncertain significance	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.715G>A is a missense variant predicted to cause substitution of Glycine by Serine at amino acid 239 (p.Gly239Ser). The filtering allele frequency (the upper threshold of the 95% CI of 9/44902) of the c.715G>A variant in ADA is 0.00008198 for East Asian 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). Another missense variant [c.716G>A], p.Gly239Asp] in the same codon has been classified as likely pathogenic for SCID by the ClinGen SCID VCEP (PM5_Supporting). Based on the above evidence, this variant may be classified as variant of uncertain significance for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP(specification version 1.0): PM2_Supporting,PM5_Supporting.
Illumina Laboratory Services, Illumina	RCV000378500	SCV000434054	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2016-06-14	criteria provided, single submitter	clinical testing	The c.715G>A (p.Gly239Ser) variant has been reported in two studies. It is found in one patient who was compound heterozygous for three variants including the p.Gly239Ser variant and the p.Arg34Ser variant in cis and a third variant in trans (Okura et al. 2011). The variant has also been reported in compound heterozygous state in the unaffected mother of a patient with adenosine deaminase deficiency. Functional studies using E. Coli found the p.Gly239Ser variant to have 1-2.2% ADA activity of wild type (Ariga et al. 2001, Hershfield et al. 2003, Okura et al. 2011, 6x). Western blot of E.Coli show the p.Gly239Ser variant combined with p.Arg34Ser has no expression (Okura et al. 2011). Control data are unavailable for this variant, which is reported at a frequency of 0.00005 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Based on the limited evidence from the literature the p.Gly239Ser variant alone is considered a partial mutation, but in cis with the p.Arg34Ser variant appears to be a complex allele. The complex allele is classified as a variant of unknown significance but suspicious for pathogenicity for adenosine deaminase deficiency.
Counsyl	RCV000378500	SCV000796301	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2017-12-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000378500	SCV001781384	uncertain significance	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-07-14	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000378500	SCV002021299	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-10-11	criteria provided, single submitter	clinical testing
Invitae	RCV000378500	SCV002305328	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 239 of the ADA protein (p.Gly239Ser). This variant is present in population databases (rs777820729, gnomAD 0.004%). This missense change has been observed in individual(s) with ADA-related conditions (PMID: 21410451). ClinVar contains an entry for this variant (Variation ID: 338506). 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: 11160213). This variant disrupts the p.Gly239 amino acid residue in ADA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26255240, 30858051). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Mendelics	RCV000378500	SCV002516213	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230481	SCV003928358	uncertain significance	not specified	2023-04-18	criteria provided, single submitter	clinical testing	Variant summary: ADA c.715G>A (p.Gly239Ser) 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 2.4e-05 in 251488 control chromosomes. c.715G>A has been reported in the literature in a paradoxical healthy carrier mother of a SCID proband who also carried G74D in trans, while the affected proband did not carry the variant of interest (Ariga_2001). This paradoxical healthy carrier displayed ADA activity in PBMC and granulocytes at about 1% of normal, however had a normal number of lymphocytes in peripheral blood and did not display any SCID phenotype. Additionally, the variant was reported in a SCID infant who carried Q119X in trans and R34S in cis (Okura_2011). From both patient reports, functional studies were performed for the variants in isolation and in combination. In both studies, ADA activity in transfected cells was reported at <10% of wild-type in transfected cells (Ariga_2001, Okura_2011). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, classifying the variant as likely pathogenic (n=3) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000378500	SCV004216781	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-09-21	criteria provided, single submitter	clinical testing