ClinVar Miner

Submissions for variant NM_000448.3(RAG1):c.1331C>T (p.Ala444Val)

gnomAD frequency: 0.00001  dbSNP: rs199474685
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV003398651 SCV004102815 pathogenic Recombinase activating gene 1 deficiency 2023-11-14 reviewed by expert panel curation The NM_000448.3(RAG1):c.1331C>T (p.Ala444Val) missense variant occurs in the NBD domain (amino acids 394-460), which is defined as a critical functional domain by the ClinGen SCID VCEP (PMID: 26996199; PM1). The popmax allele frequency is 0.00003266 (1/30614 alleles) in the South Asisan population, which is below the SCID VCEP established threshold of <0.000102 (PM2_supporting). At least 11 patients have been reported with this variant (PMIDs: 26596586, 24290284, 23085344, 17572155, 11133745, 36596882, 29410113), including patient 11 of PMID: 26596586 whom meets diagnostic criteria for SCID with a T-B-NK+ lymphocyte subset profile which is specific to recombinase activating gene 1 deficiency (PP4). Six patients are homozygous for this variant (PMIDs: 24290284, 17572155,11133745; 1pt maximum) and five are compound heterozygous (PMIDs: 26596586, 23085344, 11133745, 36596882, 29410113), harboring this variant as well as c.256_257 (provisionally classified Pathogenic by the SCID VCEP; 1+0.5pt), Val433Met, Lys992Glu, or c.2018_2025del. Total 2.5pt (PM3_Strong). Functional studies have shown a deleterious effect of this variant, significantly reducing function of the V(D)J recombination activity; mean recombination activity for Ala444Val was 1.4% of wild type +/- 0.2 (PMID: 24290284; PS3_moderate). In summary, this variant meets the criteria to be classified as pathogenic for recombinase activating gene 1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM1, PM2_supporting, PP4, PM3_Strong, PS3_Moderate. (VCEP specifications version 1).
CeGaT Center for Human Genetics Tuebingen RCV000059562 SCV001248253 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Invitae RCV001390074 SCV001591682 pathogenic Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2024-01-08 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 444 of the RAG1 protein (p.Ala444Val). This variant is present in population databases (rs199474685, gnomAD 0.003%). This missense change has been observed in individuals with primary immunodeficiency (PMID: 11133745, 23085344, 24290284, 26596586; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68681). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002281904 SCV002570605 pathogenic Severe combined immunodeficiency disease 2022-07-20 criteria provided, single submitter clinical testing Variant summary: RAG1 c.1331C>T (p.Ala444Val) results in a non-conservative amino acid change located in the RAG nonamer-binding domain (IPR023336) of 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 1.2e-05 in 250826 control chromosomes. c.1331C>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency/Atypical SCID/Omenn syndrome (example, Villa_2001, Haq_2007, Sharapova_2012, Firtina_2020). These data indicate that the variant is very 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 1.4% of normal VDJ recombination activity. Three 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003474645 SCV004200455 pathogenic Combined immunodeficiency due to partial RAG1 deficiency 2024-02-13 criteria provided, single submitter clinical testing
UniProtKB/Swiss-Prot RCV000059562 SCV000091094 not provided not provided no assertion provided not provided
Clinic of Clinical Immunology with Stem Cell Bank, Expert Centre for Rare Diseases - PID, University Hospital "Alexandrovska" RCV000559478 SCV002573422 pathogenic Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-05-01 no assertion criteria provided clinical testing

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