Submissions for variant NM_000022.4(ADA):c.956_960del (p.Glu319fs)

dbSNP: rs771266745

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000255208	SCV000224743	pathogenic	not provided	2014-09-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000255208	SCV000321381	pathogenic	not provided	2023-08-06	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 23260757, 29744787, 32888943, 26022996, 23280131, 8401541, 27484032, 8227344, 28487086, 8242080, 31858364, 32307643, 27129325, 31589614, 26255240)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173618	SCV000693974	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2016-12-30	criteria provided, single submitter	clinical testing	Variant summary: The ADA c.956_960delAAGAG (p.Glu319Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent ADA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 16/121412 control chromosomes at a frequency of 0.0001318, which does not exceed the estimated maximal expected allele frequency of a pathogenic ADA variant (0.001633). This variant has been reported in multiple SCID patients in homozgyous or compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae	RCV000173618	SCV001200277	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu319Glyfs*3) in the ADA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). This variant is present in population databases (rs771266745, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with severe combined immunodeficiency (PMID: 8401541, 27484032). This variant is also known as del nt1050-54. ClinVar contains an entry for this variant (Variation ID: 193544). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000173618	SCV001425436	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2020-02-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000255208	SCV001500263	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	ADA: PVS1, PM2, PP4
Genome-Nilou Lab	RCV000173618	SCV001977471	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	RCV000173618	SCV002021871	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2021-10-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000255208	SCV002072059	pathogenic	not provided	2020-06-26	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ADA gene demonstrated a 5 base pair deletion in exon 10, c.956_960del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 2 amino acids downstream of the mutation, p.Glu319Glyfs*3. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ADA protein with potentially abnormal function. The p.Glu319Glyfs*3 change has been reported in the gnomAD database with a frequency of 0.023% in the European sub-population (dbSNP rs912804754). This pathogenic sequence change has previously been described in the homozygous or compound heterozygous state in patients with ADA-related severe combined immunodeficiency (SCID) (PMIDs: 26255240, 8401541, 29744787).
Fulgent Genetics, Fulgent Genetics	RCV000173618	SCV002800701	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2022-04-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000173618	SCV004041408	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2023-05-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000173618	SCV000485744	likely pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2016-10-31	no assertion criteria provided	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000173618	SCV001445938	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency	2020-11-16	no assertion criteria provided	curation	This heterozygous p.Glu319GlyfsTer3 variant in ADA was identified by our study in an individual with severe combined immunodeficiency due to adenosine deaminase deficiency in the compound heterozygous state along with a likely pathogenic structural variant. The variant has been reported in at least 9 individuals with severe combined immunodeficiency due to adenosine deaminase deficiency ( PMID: 26376800, 23260757, 26255240) and with 0.02% (30/129198) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs771266745). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. The variant has also been reported in ClinVar as pathogenic by Integrated Genetics/Laboratory Corporation of America, EGL Genetic Diagnostics,Eurofins Clinical Diagnostics, and GeneDx and as likely pathogenic by Counsyl (Variation ID#: 193544). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 319 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ADA gene is an established disease mechanism in autosomal recessive severe combined immunodeficiency. The presence of this variant in at least 2 affected homozygotes and in combination with a likely pathogenic variant, and in 3 individuals with severe combined immunodeficiency increases the likelihood that p.Glu319GlyfsTer3 is pathogenic (PMID:26376800). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive severe combined immunodeficiency. ACMG/AMP Criteria applied: PVS1, PM3_strong (Richards 2015).
Natera, Inc.	RCV000173618	SCV001460804	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