Submissions for variant NM_002185.5(IL7R):c.662G>T (p.Ser221Ile)

gnomAD frequency: 0.00001  dbSNP: rs587778405

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000688209	SCV004102827	pathogenic	Immunodeficiency 104	2023-11-14	reviewed by expert panel	curation	The c.662G>T (NM_002185.5) variant in IL7R is a missense variant predicted to cause substitution of Serine by Isoleucine at amino acid 221 (p.Ser221Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). PMID 17201233: Twin B was diagnosed with SCID and was homozygous for this variant. A fraternal twin A with SCID was also reported, but the genotype of this twin was not reported. PMID 18641513: Three individuals were diagnosed with SCID and were homozygous for this variant. This variant has been detected in 7 individuals with SCID. Four individuals were homozygous for the variant (1pt maximum, PMIDs 17201233, 18641513). Two individuals recorded in the Invitae internal database were heterozygous for this variant and a c.83-2A>T variant. The c.83-2A>T variant is classified as pathogenic following the SCID-VCEP specification. The trans phase was confirmed in one patient but not the other (1.5pt in total). One individual, also from Invitae internal database, was heterozygous for this variant and a c.707-2A>G variant. The c.707-2A>G variant is classified as a pathogenic variant following the SCID-VCEP specification. The trans phase was not confirmed in this patient (0.5pt). 4pt in total, PM3_very strong is met. The individual with this variant and c.707-2A>G variant showed a T-B+NK+ lymphocyte profile, and abnormal newborn TREC result, and a diagnosis of SCID. A comprehensive SCID and CID panel did not identify an alternative cause of the disease. 1.25pt for PP4 and PP4 is met (PP4). In summary, this variant meets the criteria to be classified as pathogenic for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PM3_Very strong, PP4. (VCEP specifications version 1).
GeneDx	RCV000414042	SCV000490565	likely pathogenic	not provided	2022-11-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(S201I); This variant is associated with the following publications: (PMID: 8617735, 15661025, 19141282, 18641513, 31817502, 17201233)
Invitae	RCV000688209	SCV000815811	pathogenic	Immunodeficiency 104	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 221 of the IL7R protein (p.Ser221Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe combined immunodeficiency (SCID) (PMID: 17201233, 18641513; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 134528). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IL7R protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479011	SCV004222930	pathogenic	Severe combined immunodeficiency disease	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: IL7R c.662G>T (p.Ser221Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250914 control chromosomes. c.662G>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency (example, Lebet_2008, Ponda_2006). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17201233, 18641513). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ITMI	RCV000121217	SCV000085388	not provided	not specified	2013-09-19	no assertion provided	reference population