Submissions for variant NM_000022.4(ADA):c.478+1G>A

gnomAD frequency: 0.00003  dbSNP: rs761242509

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254941	SCV000321375	pathogenic	not provided	2017-03-28	criteria provided, single submitter	clinical testing	The c.478+1 G>A splice site variant in the ADA gene has been previously reported in association with adenosine deaminase deficiency (Santisteban et al., 1995; Grunebaum et al., 2012). This pathogenic variant destroys the canonical splice donor site in intron 5, and has been shown to cause abnormal gene splicing (Santisteban et al., 1995). The variant 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731467	SCV001339001	pathogenic	Severe combined immunodeficiency disease	2020-03-23	criteria provided, single submitter	clinical testing	Variant summary: ADA c.478+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. At least two publications report experimental evidence that this variant affects mRNA splicing and results in deletion of exon 5 (Santisteban_1995, Hirschhorn_1996). The variant allele was found at a frequency of 2.1e-05 in 193792 control chromosomes (gnomAD). c.478+1G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome (Santisteban_1995, Hirschhorn_1996, Gaspar_2011). These data indicate that the variant may be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000002055	SCV001384429	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the ADA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). 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. Disruption of this splice site has been observed in individual(s) with adenosine deaminase deficiency (PMID: 7599635, 8673127). This variant is also known as c.573+1G>A and IVS5+1GT>AT. ClinVar contains an entry for this variant (Variation ID: 265025). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000002055	SCV001977509	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
Myriad Genetics, Inc.	RCV000002055	SCV002060164	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-10-27	criteria provided, single submitter	clinical testing	NM_000022.2(ADA):c.478+1G>A is a canonical splice variant classified as pathogenic in the context of adenosine deaminase deficiency. c.478+1G>A has been observed in cases with relevant disease (PMID: 7599635, 22968453). Functional assessments of this variant are available in the literature (PMID: 7599635). c.478+1G>A has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, NM_000022.2(ADA):c.478+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000002055	SCV002557227	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0210 - Canonical splice site variant proven to affect splicing of the transcript with a known effect on protein structure. This variant is located in intron 5 of 11 and has been shown to cause skipping of exon 5, resulting in a frameshift deletion and nonsense-mediated decay (NMD) (PMID: 7599635). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (ClinVar, Decipher). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals with severe combined immunodeficiency due to ADA deficiency (ClinVar, PMID: 7599635, PMID: 8673127, PMID: 22968453, PMID: 31858364) . (P) 1002 - Moderate functional evidence supporting abnormal protein function as shown that ADA activity was reduced compared to wild-type and carriers (PMID: 8673127). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Baylor Genetics	RCV000002055	SCV004213334	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-07-05	criteria provided, single submitter	clinical testing
OMIM	RCV000002055	SCV000022213	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	1996-07-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000002055	SCV002095319	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2020-07-23	no assertion criteria provided	clinical testing