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The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_002185.5(IL7R):c.616C>T (p.Arg206Ter)

CA3232037

1298987 (ClinVar)

Gene: IL7R
Condition: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-positive, NK cell-positive
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: acd3a304-a0e9-44ee-9ecc-90e948e21b1a
Approved on: 2024-01-30
Published on: 2024-01-30

HGVS expressions

NM_002185.5:c.616C>T
NM_002185.5(IL7R):c.616C>T (p.Arg206Ter)
NC_000005.10:g.35873558C>T
CM000667.2:g.35873558C>T
NC_000005.9:g.35873660C>T
CM000667.1:g.35873660C>T
NC_000005.8:g.35909417C>T
NG_009567.1:g.21670C>T
ENST00000303115.8:c.616C>T
ENST00000303115.7:c.616C>T
ENST00000505093.1:c.25C>T
ENST00000506850.5:c.616C>T
ENST00000509668.1:n.358C>T
ENST00000514217.5:c.538-1954C>T
NM_002185.3:c.616C>T
NR_120485.1:n.641-1954C>T
NM_002185.4:c.616C>T
NR_120485.2:n.667-1954C>T
NR_120485.3:n.625-1954C>T

Pathogenic

Met criteria codes 3
PVS1 PM2_Supporting PM3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL7R Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Severe Combined Immunodeficiency Disease VCEP
The c.616C>T (p.Arg206Ter) (NM_002185.5) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_Met). The filtering allele frequency (the upper threshold of the 95% CI of 4/60022) of the c.616C>T variant in IL7R is 0.00001779 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Patients (PMIDs : 15615257,35464432, 28747913, 33628209, 32482412) were found to be homozygous for this mutation (1 pt.) (PM3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1_Met,PM2_Supporting,PM3 (VCEP specifications version 1).
Met criteria codes
PVS1
The c.616C>T (p.Arg206Ter) (NM_002185.5) variant in IL7R is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 5/8 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 Met).
PM2_Supporting
The filtering allele frequency (the upper threshold of the 95% CI of 4/60022) of the c.616C>T variant in IL7R is 0.00001779 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00004129) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
PM3
Patients (PMIDs : 15615257,35464432, 28747913, 33628209, 32482412) were found to be homozygous for this mutation (1 pt.) (PM3).
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