Submissions for variant NM_000448.3(RAG1):c.29G>T (p.Gly10Val)

gnomAD frequency: 0.00001  dbSNP: rs977780517

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765367	SCV005375441	uncertain significance	Recombinase activating gene 1 deficiency	2024-04-23	reviewed by expert panel	curation	The NM_000448.3:c.29G>T variant in RAG1 is a missense variant predicted to cause a substitution of glycine by Valine at amino acid 10 (p.Gly10Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV002304851.2). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002020935	SCV002304851	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 10 of the RAG1 protein (p.Gly10Val). This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 not expected to disrupt RAG1 protein function. ClinVar contains an entry for this variant (Variation ID: 1515226). This variant has not been reported in the literature in individuals affected with RAG1-related conditions.