Submissions for variant NM_000448.3(RAG1):c.86A>G (p.Lys29Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765373	SCV005375445	uncertain significance	Recombinase activating gene 1 deficiency	2024-04-23	reviewed by expert panel	curation	The NM_000448.3:c.86A>G variant in RAG1 is a missense variant predicted to cause a substitution of lysine by arginine at amino acid 29 (p.Lys29Arg). The Popmax filtering allele frequency of this variant in gnomAD v2.1.1 is 0.00000702, which is lower than the SCID-VCEP’s threshold for PM2 (<0.000102). No homozygous individual has been observed in the 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 two affected individuals who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV003292718.1). 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	RCV002998772	SCV003292718	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2024-06-19	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 29 of the RAG1 protein (p.Lys29Arg). This variant is present in population databases (rs756679254, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RAG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2079766). 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 with a positive predictive value of 95%. 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.