ClinVar Miner

Submissions for variant NM_000246.3(CIITA):c.2888+1G>A (rs372826934)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000594687 SCV000707580 pathogenic not provided 2017-04-10 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778455 SCV000914704 uncertain significance Bare lymphocyte syndrome 2 2018-11-22 criteria provided, single submitter clinical testing The CIITA c.2888+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.2888+1G>A variant has been reported in one study and was found in one individual with bare lymphocyte syndrome, type II in a homozygous state (Steimle et al. 1993). The variant was shown to cause a 72 bp in-frame deletion as a result of aberrant splicing. Functional studies using transfection of the variant cDNA into a CIITA-defective cell line showed that the variant cDNA did not restore HLA function and hence was shown to be inactive. Control data are unavailable for this variant, which is reported at a frequency of 0.00001064 in the total population of the Genome Aggregation Database. Based on the evidence and the potential impact of splice donor variants, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for bare lymphocyte syndrome, type II. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000778455 SCV000931656 pathogenic Bare lymphocyte syndrome 2 2020-02-11 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 13 of the CIITA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs372826934, ExAC 0.02%). This variant has been observed in an individual affected with bare lymophocyte syndrome (PMID: 8402893). ClinVar contains an entry for this variant (Variation ID: 501277). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 8402893). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CIITA are known to be pathogenic (PMID: 8402893, 9099848, 26271388). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000778455 SCV000966881 pathogenic Bare lymphocyte syndrome 2 2016-04-01 criteria provided, single submitter clinical testing The c.2888+1G>A variant in CIITA has been reported in 1 homozygous individual wi th Bare lymphocyte syndrome (also known as MHC class II immunodeficiency) and wa s shown to lead to exon skipping, predicting a 24 amino acid deletion (Steimle 1 993). This variant has also been identified in 2/116,204 of chromosomes by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs37282 6934). Although this variant has been seen in the general population, its freque ncy is low enough to be consistent with a recessive carrier frequency. In summar y, the c.2888+1G>A variant is classified as pathogenic for Bare lymphocyte syndr ome type II in an autosomal recessive manner based on case observation and funct ional analysis.

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