Submissions for variant NM_002185.5(IL7R):c.83-2A>T

gnomAD frequency: 0.00001  dbSNP: rs886060531

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000341907	SCV004098873	pathogenic	Immunodeficiency 104	2023-10-10	reviewed by expert panel	curation	The NM_002185.5(IL7R):c.83-2A>T variant occurs within the canonical splice acceptor site of intron 1. It is predicted to cause skipping of biologically relevant exon 2, resulting in a frameshift with a premature stop codon in exon 3/8, leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Patient P4, of PMID: 15661025, is homozygous for this variant (PM3_supporting). At least four probands have been reported in the literature with this variant; however, insufficient information was available to apply PP4 (PMIDs: 32888943, 24578017, 21664875, 15661025). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005649 (2/35406 alleles) in the Latino/Admixed American population, which is lower than the ClinGen SCID VCEP threshold (<0.00004129; PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PM3_supporting. (SCID VCEP specifications version 1.0).
Illumina Laboratory Services, Illumina	RCV000341907	SCV000457136	uncertain significance	Immunodeficiency 104	2016-10-03	criteria provided, single submitter	clinical testing	The IL7R c.83-2A>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.83-2A>T variant has been reported in two individuals with severe combined immune deficiency, including one who carried the variant in a compound heterozygous state with a missense variant and one who carried the variant in a heterozygous state with no second variant identified (Giliani et al. 2005; Vogel et al. 2014). The variant is reported at a frequency of 0.000058 in the Latino population of the Genome Aggregation Database. This frequency is based on two alleles in a region of good sequency coverage, so the variant is presumed to be rare. Based on the evidence from the literature and due to the potential impact of splice acceptor variants, the c.83-2A>T variant is classified as a variant of unknown significance but suspicious for pathogenicity for severe combined immune deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000485322	SCV000567902	pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 15661025, 32888943, 31817502, 24578017)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000341907	SCV002228514	pathogenic	Immunodeficiency 104	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 of the IL7R 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 IL7R are known to be pathogenic (PMID: 21664875, 26123418). This variant is present in population databases (no rsID available, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with severe combined immunodeficiency (PMID: 15661025, 24578017). This variant is also known as exon 2 -2int1 A>T. ClinVar contains an entry for this variant (Variation ID: 353259). 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.
3billion, Medical Genetics	RCV000341907	SCV003841973	pathogenic	Immunodeficiency 104	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported to be associated with IL7R related disorder (ClinVar ID: VCV000353259). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Fulgent Genetics, Fulgent Genetics	RCV000341907	SCV005671180	likely pathogenic	Immunodeficiency 104	2024-05-02	criteria provided, single submitter	clinical testing