Submissions for variant NM_000448.3(RAG1):c.2345T>A (p.Val782Asp)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003108847	SCV003783312	likely pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-08-01	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. This missense change has been observed in individual(s) with Omenn syndrome and/or severe combined immunodeficiency (PMID: 32655540). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 782 of the RAG1 protein (p.Val782Asp).
Baylor Genetics	RCV004572850	SCV005054053	likely pathogenic	Combined immunodeficiency due to partial RAG1 deficiency	2024-02-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701001	SCV005205213	likely pathogenic	Severe combined immunodeficiency disease	2024-06-14	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.2345T>A (p.Val782Asp) 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 251188 control chromosomes. c.2345T>A has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with Omenn syndrome (example, Sharapova_2020). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in undetectable RAG activity when assessed in a pro-B cell line that lacks both RAG1 and RAG2 (example, Sharapova_2020). The following publication have been ascertained in the context of this evaluation (PMID: 32655540). ClinVar contains an entry for this variant (Variation ID: 2416596). Based on the evidence outlined above, the variant was classified as likely pathogenic.