Submissions for variant NM_000448.3(RAG1):c.1303A>G (p.Met435Val)

gnomAD frequency: 0.00003  dbSNP: rs141524540

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000059561	SCV000329483	pathogenic	not provided	2020-12-09	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that M435V only has 23.6% of WT VDJ recombination activity Lee 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25976673, 17890453, 20956421, 24290284, 19178939, 22039266, 11133745, 31058115, 31388879, 32311393, 30877075, 33193364)
Fulgent Genetics, Fulgent Genetics	RCV000762842	SCV000893201	likely 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	2018-10-31	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000059561	SCV000927166	pathogenic	not provided	2017-02-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069679	SCV001234865	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 435 of the RAG1 protein (p.Met435Val). This variant is present in population databases (rs141524540, gnomAD 0.006%). This missense change has been observed in individual(s) with Omenn syndrome (PMID: 11133745, 17890453, 24290284, 28769923). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 68680). 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 have shown that this missense change affects RAG1 function (PMID: 24290284). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804802	SCV002051357	likely pathogenic	Severe combined immunodeficiency disease	2021-12-24	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.1303A>G (p.Met435Val) results in a conservative amino acid change located in the RAG nonamer-binding domain (IPR023336) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250804 control chromosomes. c.1303A>G has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (example, Villa_2001, Sheehan_2009, Haq_2007, Matangkasombut_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Lee_2014). The most pronounced variant effect results in 10%-<30% of normal VDJ recombination activity. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003474644	SCV004200466	pathogenic	Combined immunodeficiency due to partial RAG1 deficiency	2024-02-22	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059561	SCV000091093	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004734624	SCV005366227	pathogenic	RAG1-related disorder	2024-06-18	no assertion criteria provided	clinical testing	The RAG1 c.1303A>G variant is predicted to result in the amino acid substitution p.Met435Val. This variant was reported in individuals with Omenn syndrome (see for example Villa et al 2001. PubMed ID: 11133745, Lee et al 2013. PubMed ID: 24290284; Dobbs et al 2017. PubMed ID: 28769923). This variant is reported in 0.0053% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.