ClinVar Miner

Submissions for variant NM_002185.5(IL7R):c.539A>C (p.His180Pro)

gnomAD frequency: 0.00005  dbSNP: rs193922642
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV001852596 SCV004242295 uncertain significance Immunodeficiency 104 2024-01-24 reviewed by expert panel curation NM_002185.5(IL7R):c.539A>C is a missense variant predicted to cause substitution of Histidine by Proline at amino acid 180 (p.His180Pro). The highest population minor allele frequency in gnomAD v4 is 0.0002710 (16/59030 alleles) in Admixed American population (PM2_Supporting, BS1, and BA1 are not met). 2 patients (PMID: 23810098) with SCID (0.5 pt.) having T-B+NK+ lymphocyte subset profile (0.25 pt.) (Total :0.75 pts.) (PP4 not met). Both patients had maternal cell engraftment. One patient (PMID: 23810098) was found heterozygous for H180P & F71S (pre-curated as VUS) and another patient (PMID: 23810098) was found heterozygous for H180P & I94fs (not classified by SCID VCEP) (0.25 pt.). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to IL7R deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: No criteria met (VCEP specifications version 1).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030062 SCV000052717 likely pathogenic Severe combined immunodeficiency disease 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV001852596 SCV002313869 uncertain significance Immunodeficiency 104 2022-08-10 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 180 of the IL7R protein (p.His180Pro). This variant is present in population databases (rs193922642, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with IL7R-related conditions. ClinVar contains an entry for this variant (Variation ID: 36393). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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