ClinVar Miner

Submissions for variant NM_000448.2(RAG1):c.527G>T (p.Cys176Phe) (rs149229197)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413643 SCV000490762 likely pathogenic not provided 2016-04-29 criteria provided, single submitter clinical testing To our knowledge, the C176F missense variant has neither been published as a pathogenic variant, norreported as a benign polymorphism. C176F represents a non-conservative amino acid substitution as apolar Cysteine residue is replaced with a non-polar Phenylalanine residue; the loss of the Cysteine residuecould also affect normal disulfide bond formation in the protein. In addition, the position in the RAG1protein where this substitution occurs is highly conserved among species. Therefore, C176F is a strongcandidate for a pathogenic variant; however, the possibility that it is a benign variant cannot beexcluded.
Invitae RCV000792591 SCV000931897 uncertain significance Combined cellular and humoral immune defects with granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 176 of the RAG1 protein (p.Cys176Phe). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs149229197, ExAC 0.001%). This variant has been observed in individuals affected with severe combined immunodeficiency (SCID) and delayed onset combined immunodeficiency with autoimmune/granulomatous manifestations (CID-G/AI) (PMID: 28769923, 26457731, Invitae). ClinVar contains an entry for this variant (Variation ID: 372487). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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