Submissions for variant NM_000448.3(RAG1):c.1856C>T (p.Pro619Leu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002966260	SCV003277728	likely pathogenic	Combined immunodeficiency with skin granulomas; Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 619 of the RAG1 protein (p.Pro619Leu). This variant is present in population databases (rs755059628, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of severe combined immunodeficiency (PMID: 33117328). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2066890). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235750	SCV003934519	uncertain significance	not specified	2023-05-01	criteria provided, single submitter	clinical testing	Variant summary: RAG1 c.1856C>T (p.Pro619Leu) 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 1.2e-05 in 251358 control chromosomes. c.1856C>T has been reported in the literature in a compound heterozygous individual who was affected with atypical Severe Combined Immunodeficiency. The patient carried the variant in trans with another pathogenic allele, with the variant allele showing reduced recombination activity (40% of WT) (Chitty-Lopez_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33117328, 35902638, 32633164). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.