Submissions for variant NM_000448.3(RAG1):c.40G>A (p.Ala14Thr)

dbSNP: rs765396585

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV004765358	SCV005375442	uncertain significance	Recombinase activating gene 1 deficiency	2024-04-23	reviewed by expert panel	curation	The NM_000448.3:c.40G>A variant in RAG1 is a missense variant predicted to cause a substitution of alanine by threonine at amino acid 14 (p.Ala14Thr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000008797 (1/113676 alleles) in the European (non-Finnish) population, which is lower than the SCID-VCEP threshold (<0.000102) for PM2_Supporting. 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 one affected individual who didn't have a second RAG1 variant, and the variant was classified as a Variant of Uncertain Significance (Invitae, SCV002113580.2). 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	RCV002050837	SCV002113580	uncertain significance	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2022-03-19	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals affected with RAG1-related conditions. This variant is present in population databases (rs765396585, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 14 of the RAG1 protein (p.Ala14Thr).
Ambry Genetics	RCV003339760	SCV004059436	uncertain significance	Inborn genetic diseases	2023-06-27	criteria provided, single submitter	clinical testing	The c.40G>A (p.A14T) alteration is located in exon 2 (coding exon 1) of the RAG1 gene. This alteration results from a G to A substitution at nucleotide position 40, causing the alanine (A) at amino acid position 14 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.