Submissions for variant NM_000448.3(RAG1):c.1438A>G (p.Ser480Gly)

dbSNP: rs772340017

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000171192	SCV000221389	likely pathogenic	not provided		criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852063	SCV002178445	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2021-08-19	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with clinical features of RAG1-related conditions (PMID: 24331380, 31130284). This variant is present in population databases (rs772340017, ExAC 0.001%). This sequence change replaces serine with glycine at codon 480 of the RAG1 protein (p.Ser480Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. ClinVar contains an entry for this variant (Variation ID: 191017). 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 RAG1 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993851	SCV004813596	likely pathogenic	Severe combined immunodeficiency disease	2024-02-28	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.1438A>G (p.Ser480Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of four 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 251122 control chromosomes. c.1438A>G has been reported in the literature at a homozygous state in at-least two individuals affected with Severe Combined Immunodeficiency (Monies_2019, Schuetz_2023, Schuetz_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 55% of normal V(D)J recombination activity in human primary dermal fibroblasts (Schuetz_2023, Schuetz_2014). The following publications have been ascertained in the context of this evaluation (PMID: 31130284, 36279417, 24331380). ClinVar contains an entry for this variant (Variation ID: 191017). Based on the evidence outlined above, the variant was classified as likely pathogenic.