Submissions for variant NM_000536.4(RAG2):c.14T>A (p.Met5Lys)

gnomAD frequency: 0.00019  dbSNP: rs143415103

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765327	SCV005375461	uncertain significance	Recombinase activating gene 2 deficiency	2024-05-01	reviewed by expert panel	curation	NM_000536.4(RAG2):c.14T>A is a missense variant predicted to cause substitution of Methionine by Lysine at amino acid 5 (p.Met5Lys). This missense variant is located in the core domain (amino acids 1-383) (PM1_supporting).The highest population minor allele frequency in gnomAD v4 is 0.0003307 (389/1176246) in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). To our knowledge, this variant has not been reported in the literature in individuals affected with RAG2 related conditions or in functional studies. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG2 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_supporting (VCEP specifications version 1).
Illumina Laboratory Services, Illumina	RCV000330271	SCV000371808	uncertain significance	Histiocytic medullary reticulosis	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001731472	SCV000371809	uncertain significance	Severe combined immunodeficiency disease	2016-06-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689525	SCV000817179	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 5 of the RAG2 protein (p.Met5Lys). This variant is present in population databases (rs143415103, gnomAD 0.03%). 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: 304560). 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 expected to disrupt RAG2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.	RCV000330271	SCV001458525	uncertain significance	Histiocytic medullary reticulosis	2020-03-11	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528918	SCV001741486	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528918	SCV001965608	uncertain significance	not provided		no assertion criteria provided	clinical testing