Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000801211 | SCV000940977 | pathogenic | Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive | 2022-08-23 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with severe combined immunodeficiency (SCID) (PMID: 18701881, 32445296). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918572, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 776 of the RAG1 protein (p.Arg776Trp). This variant is also known as C2438T. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg776 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been observed in individuals with RAG1-related conditions (PMID: 17572155, 19458910), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects RAG1 function (PMID: 18701881). 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 RAG1 protein function. ClinVar contains an entry for this variant (Variation ID: 13161). |
| Baylor Genetics | RCV003473098 | SCV004200515 | pathogenic | Combined immunodeficiency due to partial RAG1 deficiency | 2023-02-25 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004689417 | SCV005185382 | pathogenic | Severe combined immunodeficiency disease | 2024-05-30 | criteria provided, single submitter | clinical testing | Variant summary: RAG1 c.2326C>T (p.Arg776Trp) 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 allele was found at a frequency of 4e-06 in 251212 control chromosomes. c.2326C>T has been reported in the literature in the homozygous and presumed compound heterozygous states in multiple individuals affected with Severe Combined Immunodeficiency and/or Omenn syndrome (example, Firtina_2020, Karaatmaca_2024, Suratannon_2020, Xiao_2009). 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: 32445296, 37724703, 32373116, 18701881). ClinVar contains an entry for this variant (Variation ID: 13161). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV005042046 | SCV005683487 | pathogenic | Combined immunodeficiency due to partial RAG1 deficiency; Combined immunodeficiency with skin granulomas; Histiocytic medullary reticulosis; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive | 2024-06-01 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000014047 | SCV000034294 | pathogenic | Severe combined immunodeficiency, B cell-negative | 2009-02-01 | no assertion criteria provided | literature only |