Submissions for variant NM_000448.3(RAG1):c.1677G>T (p.Arg559Ser)

dbSNP: rs199474681

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV001594380	SCV001499912	pathogenic	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2020-12-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854249	SCV002228683	pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 559 of the RAG1 protein (p.Arg559Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Omenn syndrome and/or severe combined immunodeficiency (PMID: 11133745, 11520796, 24290284, 24418478). ClinVar contains an entry for this variant (Variation ID: 68685). 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. 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	RCV003230391	SCV003928985	pathogenic	Severe combined immunodeficiency disease	2023-04-26	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.1677G>T (p.Arg559Ser) results in a non-conservative amino acid change in 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 4e-06 in 250910 control chromosomes. c.1677G>T has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (Alsmadi_2009, Kumaki_2001, Lee_2014, Villa_2001). 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 demonstrating that this change affects RAG1 function (Lee_2014). The following publications have been ascertained in the context of this evaluation (PMID: 19912631, 11520796, 24290284, 11133745). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
UniProtKB/Swiss-Prot	RCV000059566	SCV000091098	not provided	not provided		no assertion provided	not provided