ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs141524540
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Total submissions: 7
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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
Invitae RCV001069679 SCV001234865 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2023-11-20 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). 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 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

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