Submissions for variant NM_000022.4(ADA):c.95+1G>A

dbSNP: rs778343059

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670969	SCV000795900	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2017-11-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731875	SCV001370571	pathogenic	Severe combined immunodeficiency disease	2020-05-14	criteria provided, single submitter	clinical testing	Variant summary: ADA c.95+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. At least one publication reports that this variant disrupts a 5 splice donor site, causing exon 2 skipping and activation of a cryptic splice site. However, the authors also report that some normal pre-mRNA splicing may also occur (perhaps because of the block in the second step of splicing being leaky to a slight degree) which accounts for the phenotypic variability in patients (Arredondo-Vega_1994). The variant was absent in 244702 control chromosomes (gnomAD). c.95+1G>A has been reported in the literature in two siblings affected with Severe Combined Immunodeficiency Syndrome (severely and mildly affected) and an individual with atypical severe immunodeficiency (Arredondo-Vega_1994, Felgentreff_2011). These data indicate that the variant may be associated with disease. One ClinVar submitter (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000670969	SCV001977522	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
Invitae	RCV000670969	SCV002196292	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-11-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in insertion of four nucleotides at the exon 2/3 junction and introduces a premature termination codon (PMID: 8178821). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 555196). Disruption of this splice site has been observed in individual(s) with adenosine deaminase deficiency (PMID: 8178821). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the ADA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
OMIM	RCV000670969	SCV000022209	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	1994-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000670969	SCV002095338	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-06-30	no assertion criteria provided	clinical testing