Submissions for variant NM_002185.5(IL7R):c.778G>A (p.Ala260Thr)

gnomAD frequency: 0.00144  dbSNP: rs147153824

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001087188	SCV004102832	likely benign	Immunodeficiency 104	2023-11-14	reviewed by expert panel	curation	The c.778G>A (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Alanine by Threonine at amino acid 260 (p.Ala260Thr). The filtering allele frequency (the lower threshold of the 95% CI of 115/24962) of the c.778G>A variant in IL7R is 0.003885 in exomes and 0.003267 in genomes (no homozygous reported) for African/African American chromosomes by gnomAD v2.1.1. Both values are higher than the ClinGen SCID VCEP threshold (0.00126) for BS1 and therefore meet this criterion (BS1). The variant has not been identified in the literature. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BS1. (VCEP specifications version 1).
GeneDx	RCV000480034	SCV000565075	uncertain significance	not provided	2019-08-12	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV001087188	SCV000761661	likely benign	Immunodeficiency 104	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001087188	SCV001315712	likely benign	Immunodeficiency 104	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001087188	SCV001468348	uncertain significance	Immunodeficiency 104	2021-03-30	criteria provided, single submitter	clinical testing	IL7R NM_002185.4 exon 6 p.Ala260Thr (c.778G>A): This variant has not been reported in the literature but is present in 0.4% (115/24962) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-35874622-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:418258). This variant amino acid Threonine (Thr) is present in 5 species (Chinese hamster, Golden hamster, Elephant, Elephant shrew, Manatee) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.