Submissions for variant NM_000448.3(RAG1):c.2258A>T (p.His753Leu)

gnomAD frequency: 0.00003  dbSNP: rs199474687

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687602	SCV000815179	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2025-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 753 of the RAG1 protein (p.His753Leu). This variant is present in population databases (rs199474687, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of RAG1-related conditions (PMID: 11133745; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as A2370T. ClinVar contains an entry for this variant (Variation ID: 68690). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAG1 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RAG1 function (PMID: 11971977). This variant disrupts the p.His753 amino acid residue in RAG1. Other variant(s) that disrupt this residue have been observed in individuals with RAG1-related conditions (PMID: 24144642), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271397	SCV002556102	uncertain significance	not specified	2022-06-23	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.2258A>T (p.His753Leu) results in a non-conservative amino acid change located in the Zinc Finger B region of the Core Central (CD) domain (Kumar_2015) 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 251410 control chromosomes (gnomAD). c.2258A>T has been reported in the literature in at least one compound heterozygous individual affected with atypical Severe Combined Immunodeficiency (Villa_2001). These data do not allow any conclusion about variant significance. One publication reports that disruption of the highly conserved corresponding amino acid in mouse RAG1 severely impacted DNA binding (15-50 fold decrease, Huye_2002). One ClinVar submitter has assessed the variant since 2014: the variant was classified as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003474651	SCV004200453	likely pathogenic	Combined immunodeficiency due to partial RAG1 deficiency	2024-02-12	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059571	SCV000091103	not provided	not provided		no assertion provided	not provided