ClinVar Miner

Submissions for variant NM_000536.4(RAG2):c.814G>A (p.Val272Ile)

dbSNP: rs117899975
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001043775 SCV001207537 uncertain significance Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2022-09-27 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 272 of the RAG2 protein (p.Val272Ile). This variant is present in population databases (rs117899975, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with RAG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 841530). 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 RAG2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc. RCV001274396 SCV001458519 uncertain significance Histiocytic medullary reticulosis 2020-01-24 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357399 SCV001552865 uncertain significance not provided no assertion criteria provided clinical testing The RAG2 p.Val272Ile variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs117899975) and in Cosmic (confirmed somatically in pancreas carcinoma tumour sample; FATHMM prediction of pathogenic, score 0.95). The variant was also identified in control databases in 48 of 282752 chromosomes at a frequency of 0.00017 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 35 of 19948 chromosomes (freq: 0.001755), South Asian in 12 of 30616 chromosomes (freq: 0.000392) and European (non-Finnish) in 1 of 129116 chromosomes (freq: 0.000008), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish) or Other populations. The p.Val272 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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