ClinVar Miner

Submissions for variant NM_000022.4(ADA):c.956_960del (p.Glu319fs) (rs771266745)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255208 SCV000224743 pathogenic not provided 2014-09-24 criteria provided, single submitter clinical testing
GeneDx RCV000255208 SCV000321381 pathogenic not provided 2019-02-06 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, 26022996, 23280131, 8401541, 27484032, 8227344, 28487086, 8242080, 31858364, 32307643)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000173618 SCV000693974 pathogenic Severe combined immunodeficiency due to ADA 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 due to ADA deficiency 2020-10-08 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. This variant is present in population databases (rs771266745, ExAC 0.02%). This variant has been observed in individuals affected with severe combined immunodeficiency (PMID: 8401541, 27484032). This variant is also known as del nt1050-54 in the literature. ClinVar contains an entry for this variant (Variation ID: 193544). Loss-of-function variants in ADA are known to be pathogenic (PMID: 26255240, 26376800). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV000173618 SCV001425436 pathogenic Severe combined immunodeficiency due to ADA deficiency 2020-02-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255208 SCV001500263 pathogenic not provided 2021-01-01 criteria provided, single submitter clinical testing
Counsyl RCV000173618 SCV000485744 likely pathogenic Severe combined immunodeficiency due to ADA deficiency 2016-10-31 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000173618 SCV001445938 pathogenic Severe combined immunodeficiency due to ADA 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 due to ADA deficiency 2020-09-16 no assertion criteria provided clinical testing

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